Compounds useful as inhibitors of indoleamine 2,3-dioxygenase

ABSTRACT

The present invention relates to compounds useful as inhibitors of indoleamine 2,3-dioxygenase (IDO). The invention also relates to pharmaceutically acceptable compositions comprising the compounds of this invention; methods of treating of various diseases, disorders, and conditions using the compounds of this invention; processes for preparing the compounds of this invention; intermediates for the preparation of the compounds of this invention; and methods of using the compounds in in vitro applications. 
     The compounds of this invention have formula I-A: 
     
       
         
         
             
             
         
       
     
     wherein the variables are as defined herein.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit of under 35 U.S.C. §119 U.S.Provisional Application No. 61/728,333, filed Nov. 20, 2012, as well asU.S. Provisional Application No. 61/757,764, filed Jan. 29, 2013.

BACKGROUND OF THE INVENTION

Tryptophan (Trp) is an essential amino acid necessary for thebiosynthesis of proteins, niacin, and the neurotransmitter5-hydroxytryptamine (serotonin). The heme-dependent oxygenaseindoleamine 2,3-dioxygenase (also named INDO or IDO) is responsible forthe extra-hepatic conversion of Trp to N-formyl-kynurenine as arate-limiting first step of Trp metabolism. N-formyl-kynurenine is aprecursor of a variety of bioactive molecules called kynurenines thathave immunomodulatory properties (Schwarcz et al., Nat Rev Neurosci.2012; 13(7):465-77).

IDO was initially described as part of the mammalian defense mechanismagainst parasite infection. Depletion of Trp can lead to growth arrestof intracellular pathogens such as Toxoplasma gondii or Chlamydiatrachomatis (MacKenzie et al., Curr Drug Metab. 2007; 8(3):237-44). Morerecently, it has become apparent that IDO is an inducible enzyme thathas a primary role in immune cell modulation. The reduction of Trplevels and increase in the pool of kynurenines cause inhibition ofeffector immune cells and promote adaptive immune suppression throughinduction and maintenance of regulatory T cells (Tregs; Munn, FrontBiosci. 2012; 4:734-45).

Increased turnover of Trp to kynurenines by IDO has been observed in anumber of disorders linked to activation of the immune system, e.g.infection, malignancy, autoimmune diseases, trauma and AIDS (Johnson andMunn, Immunol Invest 2012; 41(6-7): 765-97). Additional studies in theseindications have shown that induction of IDO results in suppression ofT-cell responses and promotion of tolerance. In cancer, for example, alarge body of evidence suggests that IDO upregulation serves as amechanism in tumour cells to escape immune surveillance. IDO isexpressed widely in solid tumours (Uyttenhove et al., Nat Med. 2003;10:1269-74) and has been observed in both primary and metastatic cancercells. IDO is induced in tumours by proinflammatory cytokines, includingtype I and type II interferons that are produced by infiltratinglymphocytes (Tnani and Bayard, Biochim Biophys Acta. 1999;1451(1):59-72; Mellor and Munn, Nat Rev Immunol 2004; 4(10):762-74;Munn, Front Biosci. 2012; 4:734-45) and TGF-Beta (Pallotta et al., NatImmunol. 2011; 12(9):870-8). Certain oncogenic mutations can also leadto increased IDO expression, e.g., loss of the tumour suppressor Binl(Muller et al, Nat Med. 2005; 11(3):312-9) or activating mutations inKIT (Balachandran et al., Nat Med. 2011; 17(9): 1094-1100). IDOexpression has been correlated with immune anergy in some tumours (e.g.Ino et al., Clin Cancer Res. 2008 Apr. 15; 14(8):2310-7; Brandacher etal., Clin. Cancer Res. 2006 Feb. 15; 12(4):1144-51.), and a recentreport has shown that reduction of IDO expression in humangastrointestinal tumours goes along with an increased infiltration oftumours by effector T cells (Balachandran et al., Nat Med. 2011; 17(9):1094-1100).

A significant amount of preclinical data has been published that furthervalidates the role of IDO in the anti-tumour immune response. Forexample, forced IDO induction in cancer cells was shown to confer asurvival advantage (Uyttenhove et al., Nat Med. 2003; 10:1269-74). Otherin vivo studies showed that IDO inhibitors cause lymphocyte dependentreduction in tumour growth by lowering kynurenine levels (Liu et al.,Blood. 2010; 115(17):3520-30). Preclinical studies also highlighted thescope for IDO inhibitors to work synergistically in combination withagents that promote tumour antigenicity like irradiation, chemotherapyor vaccines (Koblish et al., Mol Cancer Ther. 2010; 9(2):489-98, Hou etal., Cancer Res. 2007; 67(2):792-801; Sharma et al., Blood. 2009;113(24):6102-11).

In addition to creating an immune suppressive environment in tumours,IDO has also been implicated in inducing tolerance in lymph nodes, aphenomenon that seems to further contribute to immune evasion in cancer(Munn, Curr Opin Immunol. 2006; 18(2):220-5). IDO expression has beenreported in antigen presenting cells, e.g. dendritic cells (DCs), whichmigrate to lymph nodes and induce anergy. IDO-positive DCs in tumourdraining lymph nodes (TDLNs) of cancer-bearing mice have been shown toprevent the conversion of Tregs to inflammatory T-helper-17 (Th17)-likecells (Sharma et al., Blood. 2009; 113(24):6102-11), thereby blockingT-cell activation. Conversion of Tregs into proinflammatory Th17-likecells occurred when IDO activity was blocked with the IDO inhibitor1-MT. IDO activity in TDLNs therefore provides an important aspect ofthe rationale for its inhibition as a cancer therapy.

IDO-mediated formation of kynurenines has recently also been implicatedin mechanisms beyond the regulation of the immune system. For example,numerous studies since the 1970s have demonstrated that kynurenines caninfluence brain function. Kynurenine pathway metabolites are now seen aspotential causative factors in several devastating brain diseases.Fluctuations in the level of kynurenine pathway metabolites can lead tothe deterioration of physiological processes and the emergence ofpathological states, e.g., neurodegenerative diseases, schizophrenia anddepression (Schwarcz et al., Nat Rev Neurosci. 2012; 13(7):465-77).Furthermore, IDO-mediated kynurenine production in blood vessels hasbeen linked to vasodilation and shock in inflammation and sepsis (Wanget al., Nat. Med 2010; 16(3):279-85). IDO expression has been observedin resistance vessels in human sepsis, and IDO activity correlates withhypotension in human septic shock (Changsirivathanathamrong et al., CritCare Med. 2011; 39(12):2678-830). In clinical studies with sepsis andbacteremia patients, IDO-mediated tryptophan catabolism has beenassociated with dysregulated immune responses and impaired microvascularreactivity (Darcy et al., PLoS One. 2011; 6(6):e21185), as well assurvival and disease severity (Huttunen et al., Shock. 2010;33(2):149-54). Similarly, in community acquired pneumonia patients, IDOactivity correlates with negative outcome and disease progression,including sepsis severity (Suzuki et al., J Infect. 2011;63(3):215-22.). There is therefore a strong rationale for inhibition ofIDO activity in bacterial infections and sepsis.

Taken together, there is a need for the development of potent andselective IDO inhibitors, either as single agents or combinationtherapies, to modulate the kynurenine pathway and maintain physiologicaltryptophan levels in the body to more effectively combat diseases andconditions resulting from the harmful products of the kynureninepathway, abnormal deviations in the levels of kynurenine pathwaymetabolites, or decreases in tryptophan levels. Such inhibitorscounteract immune suppression, vasodilation and neurotoxicity that havebeen linked to the activity and expression of the IDO enzyme.

SUMMARY OF THE INVENTION

This invention relates to compounds and compositions useful asindoleamine 2,3-dioxygenase (IDO) inhibitors. The invention also relatesto pharmaceutically acceptable compositions comprising the compounds ofthis invention; processes for preparing the compounds of this invention;intermediates for the preparation of the compounds of this invention;methods of using the compounds in in vitro applications, such as thestudy of IDO1 in biological and pathological phenomena; and the study ofintracellular signal transduction.

Moreover, these compounds and pharmaceutically acceptable compositionsthereof are very potent IDO inhibitors and are useful for treating orpreventing a variety of diseases, disorders or conditions including, butnot limited to, cancer and sepsis.

DETAILED DESCRIPTION OF THE INVENTION

This invention describes compounds of Formula I-A:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:n is 0-4;X is halo;

Z¹, Z², and Z³ are CH or N;

R¹ is independently selected from halo; —CN; Q^(X); or a C₁₋₁₀aliphaticchain wherein up to four methylene units of the aliphatic chain areoptionally replaced with —O—, —NR—, —S—, —C(O)—, S(O)—, or —S(O)₂—; R¹is optionally substituted with 0-5 J¹ groups;Q^(X) is a 3-7 membered monocyclic fully saturated, partiallyunsaturated, or aromatic ring containing 0-3 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur;J¹ is independently selected from halo; —CN; Q^(Y); or a C₁₋₆aliphaticchain wherein up to three methylene units of the aliphatic chain areoptionally replaced with —O—, —NR—, —S—, —C(O)—, —S(O)—, or —S(O)₂—; J¹is optionally substituted with 0-5 J² groups; ortwo occurrences of J¹ on the same atom, together with the atom to whichthey are attached, form a 3-6 membered non-aromatic monocyclic ring; thering formed by two occurrences of J¹ on the same atom is optionallysubstituted with 0-3 J^(2A) groups; ortwo occurrences of J¹, together with Q^(X), form a bridged ring system;Q^(Y) is independently selected from a 3-7 membered monocyclic fullysaturated, partially unsaturated, or aromatic ring containing 0-3heteroatoms independently selected from nitrogen, oxygen, or sulfur; oran 8-12 membered bicyclic fully saturated, partially unsaturated, oraromatic ring containing 0-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur;J² is independently selected from halo; ═O; —CN; a 3-6 membered aromaticor non-aromatic ring containing 0-3 heteroatoms selected from oxygen,nitrogen, or sulfur; or C₁₋₄aliphatic chain wherein up to two methyleneunits of the aliphatic chain are optionally replaced with —O—, —NR—,—S—, —C(O)—, S(O)—, or —S(O)₂—; J² is optionally substituted with 0-5 J³groups; ortwo occurrences of J², together with the atom or atoms to which they areattached, form a 3-6 membered aromatic or non-aromatic monocyclic ring;the ring formed by two occurrences of J² is optionally substituted with0-3 J^(3A) groups; ortwo occurrences of J², together with Q^(Y), form a bridged ring system;J^(2A) is independently selected from halo or a C₁₋₄aliphatic chainwherein up to two methylene units of the aliphatic chain are optionallyreplaced with —O—, —NR—, —S—, —S(O)—, —S(O)₂, or —C(O);J³ and J^(3A) are independently selected from halo or C₁₋₄alkyl; andR is independently selected from H or C₁₋₆aliphatic.

For purposes of this application, it will be understood that when twooccurrences of J¹, together with Q^(X), form a bridged ring system, thetwo occurrences of J¹ are attached to separate atoms of Q^(X). Moreover,when two occurrences of J², together with Q^(Y), form a bridged ringsystem, the two occurrence of J² are attached to separate atoms ofQ^(Y).

In some embodiments, the present invention is a compound of formula I-A,wherein Z¹, Z², and Z³ are CH. In other embodiments, the presentinvention is a compound of formula I-A, wherein Z¹ and Z² are CH and Z³is nitrogen. In another embodiment, the present invention is a compoundof formula I-A, wherein Z¹ and Z² are nitrogen and Z³ is CH. In yetanother embodiment, the present invention is a compound of formula I-A,wherein Z¹ and Z³ are CH and Z² is nitrogen. It will be understood thatthroughout the application Z¹, Z², or Z³ can be substituted with R¹ whenZ¹, Z², or Z³ is CH.

In another embodiment, the present invention is a compound of formulaI-A, wherein X is selected from bromo or chloro. In other embodiments,the present invention is a compound of formula I-A, wherein X is bromo.In yet another embodiment, the present invention is a compound offormula I-A, wherein X is chloro.

In some embodiments, the present invention is a compound of formula I-A,wherein n is 0.

In another embodiment, the present invention is a compound of formulaI-A, wherein R¹ is independently selected from halo, —CN, or aC₁₋₈aliphatic chain wherein up to four methylene units of the aliphaticchain are optionally replaced with —O—, —NR—, —C(O)—, or —S(O)₂—.

In some embodiments, the present invention is a compound of formula I-A,wherein R¹ is a C₁₋₆aliphatic chain wherein up to three methylene unitsof the aliphatic chain are optionally replaced with —O—, —NR—, —C(O)—,or S(O)₂. In another embodiment, the present invention is a compound offormula I-A, wherein R¹ is independently selected from C₁₋₆alkyl,—(C₁₋₄alkyl)O(C₁₋₄alkyl), —NHSO₂(C₁₋₄alkyl),—(C₁₋₄alkyl)NHC(O)(C₁₋₄alkyl), —CO₂(C₁₋₄alkyl),—(C₁₋₄alkyl)NHSO₂(C₁₋₄alkyl), —(C₁₋₄alkyl)SO₂NH(C₁₋₄alkyl),—C(O)NH(C₁₋₄alkyl), —C(O)NH, —O(C₁₋₄alkyl),—(C₁₋₄alkyl)NHCO₂(C₁₋₄alkyl), —SO₂(C₁₋₄alkyl), —(C₁₋₄alkyl)CH(O),—(C₁₋₄alkyl)NH₂, —(C₁₋₄alkyl)OH, —(C₁₋₄alkyl)C(O)OH, or —C(O)NH₂.

In yet another embodiment, the present invention is a compound offormula I-A, wherein R¹ is independently selected from C₁₋₆alkyl,—(C₁₋₄alkyl)O(C₁₋₄alkyl), —(C₁₋₄alkyl)SO₂NH(C₁₋₄alkyl),—(C₁₋₄alkyl)NHC(O)(C₁₋₄alkyl), —(C₁₋₄alkyl)NHSO₂(C₁₋₄alkyl),—(C₁₋₄alkyl)NHCO₂(C₁₋₄alkyl), or —O(C₁₋₄alkyl). In some embodiments, thepresent invention is a compound of formula I-A, wherein R¹ isindependently selected from C₁₋₆alkyl, —O(C₁₋₄alkyl), or—(C₁₋₄alkyl)O(C₁₋₄alkyl).

In another embodiment, the present invention is a compound of formulaI-A, wherein R¹ is —CN.

In other embodiments, the present invention is a compound of formulaI-A, wherein R¹ is halo.

In some embodiments, the present invention is a compound of formula I-A,wherein J¹ is independently selected from halo, a C₁₋₆aliphatic, orQ^(Y).

In one embodiment, the present invention is a compound of formula I-A,wherein J¹ is halo. In other embodiments, J¹ is fluoro.

In some embodiments, the present invention is a compound of formula I-A,wherein J₁ is a C₁₋₆aliphatic.

In yet another embodiment, the present invention is a compound offormula I-A, wherein J¹ is Q^(Y). In some embodiments, the presentinvention is a compound of formula I-A, wherein Q^(Y) is independentlyselected from a 5-6 membered aryl or heteroaryl, a 3-7 memberedcycloaliphatic, or a 3-7 membered heterocyclyl; the heteroaryl andheterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, orsulfur.

In another embodiment, the present invention is a compound of formulaI-A, wherein Q^(Y) is independently selected from a 3-7 memberedcycloaliphatic or a 3-7 membered heterocyclyl having 1-2 heteroatomsindependently selected from oxygen, nitrogen, or sulfur. In someembodiments, the present invention is a compound of formula I-A, whereinQ^(Y) is independently selected from cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, piperidinyl, azepanyl,pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrazolidinyl,isoxazolidinyl, thiazolidinyl, imidazolidinyl, 1,4-diazepanyl,1,4-oxazepanyl, 1,4-thiazepanyl, 1,3-oxazinanyl, or 1,3-thiazinanyl. Inother embodiments, the present invention is a compound of formula I-A,wherein Q^(Y) is independently selected from cyclobutyl, piperazinyl, ormorpholinyl.

In some embodiments, the present invention is a compound of formula I-A,wherein Q^(Y) is a 5-6 membered aryl or heteroaryl. In otherembodiments, the present invention is a compound of formula I-A, whereinJ¹ is independently selected from phenyl, pyrrolyl, pyridinyl,isoxazolyl, pyrimidinyl, imidazolyl, pyrazinyl, or pyrazolyl. In oneembodiment, the present invention is a compound of formula I-A, whereinQ^(Y) is phenyl.

In yet another embodiment, the present invention is a compound offormula I-A, wherein J² is halo.

In other embodiments, the present invention is a compound of formulaI-A, wherein J² is a 3-6 membered aromatic or non-aromatic monocyclicring having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur.In another embodiment, the present invention is a compound of formulaI-A, wherein J² is independently selected from cyclopropyl, cyclobutyl,or phenyl.

In some embodiments, the present invention is a compound of formula I-A,wherein J² is independently selected from a C₁₋₄aliphatic chain whereinup to two methylene units of the aliphatic chain are optionally replacedwith —O—, —NR—, —S—, —C(O)—, —S(O)— or S(O)₂. In another aspect, thepresent invention is a compound of formula I-A, wherein J² isindependently selected from —C(O)OH or —C₁₋₄alkyl.

In another example, the invention describes compounds of formula I-Ahaving the formula:

or a pharmaceutically acceptable salt or prodrug thereof, wherein

X is bromo or chloro.

In some embodiments, Z¹ and Z² of formula I-B are nitrogen. In otherembodiments, only one of Z¹ or Z² of formula I-B is nitrogen. In yetanother embodiment, Z¹ and Z² of formula I-B are CH.

In another example, X of formula I-B is chloro.

In yet another aspect, n of formula I-B is 0.

In another embodiment, R¹ of formula I-B is independently selected fromhalo, —CN, or a C₁₋₈aliphatic chain wherein up to four methylene unitsof the aliphatic chain are optionally replaced with —O—, —NR—, —C(O)—,or —S(O)₂—.

In yet another example, R¹ of formula I-B is a C₁₋₆aliphatic chainwherein up to four methylene units of the aliphatic chain are optionallyreplaced with —O—, —NR—, —C(O)—, or —S(O)₂—. In some embodiments, R¹ offormula I-B is independently selected from C₁₋₆alkyl,—(C₁₋₄alkyl)O(C₁₋₄alkyl), —(C₁₋₄alkyl)OH, —O(C₁₋₄alkyl),—(C₁-4alkyl)SO₂NH(C₁₋₄alkyl), —(C₁₋₄alkyl)NHC(O)(C₁₋₄alkyl),—(C₁₋₄alkyl)NHSO₂(C₁₋₄alkyl), —(C₁₋₄alkyl)NHCO₂(C₁₋₄alkyl), or—(C₁₋₄alkyl)C(O)OH. In another embodiment, R¹ of formula I-B isindependently selected from C₁₋₆alkyl, —O(C₁₋₄alkyl), or—(C₁₋₄alkyl)O(C₁₋₄alkyl).

In another aspect, R¹ of formula I-B is —CN.

In another example, R¹ of formula I-B is halo.

In some embodiments, J¹ of formula I-B is independently selected fromhalo, a C₁₋₆aliphatic, or a 3-7 membered aromatic or non-aromatic ringcontaining 0-4 heteroatoms independently selected from nitrogen, oxygen,or sulfur.

In one embodiment, J₁ of formula I-B is C₁₋₆aliphatic. In anotherembodiment, J₁ of formula I-B is C₁₋₄alkyl.

In other embodiments, J¹ of formula I-B is a 3-6 membered cycloaliphaticor a 3-6 membered heterocyclyl having 1-2 heteroatoms selected fromoxygen, nitrogen, or sulfur. In another embodiment, J¹ of formula I-B isindependently selected from cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, orthiomorpholinyl. In yet another embodiment, J¹ of formula I-B isindependently selected from cyclobutyl, piperazinyl, or morpholinyl.

In another example, the compounds of this invention are represented inTable 1. It will be appreciated by those skilled in the art that thecompounds of the present invention may be represented in varyingtautomeric forms.

TABLE 1

I-1

I-2

I-3

I-4

I-5

I-6

I-7

I-8

I-9

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

I-25

I-26

I-27

I-28

I-29

I-30

I-31

I-32

I-33

I-34

I-35

I-36

I-37

I-38

I-39

I-40

I-41

I-42

I-43

I-44

I-45

I-46

I-47

I-48

Compounds of this invention include those described generally herein andare further illustrated by the classes, subclasses, and speciesdisclosed herein. As used herein, the following definitions shall applyunless otherwise indicated. For purposes of this invention, the chemicalelements are identified in accordance with the Periodic Table of theElements, CAS version, Handbook of Chemistry and Physics, 75^(th) Ed.Additionally, general principles of organic chemistry are described in“Organic Chemistry”, Thomas Sorrell, University Science Books,Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^(th) Ed.:Smith and March, John Wiley & Sons, New York: 2001, the entire contentsof which are hereby incorporated by reference.

As described herein, a specified number range of atoms includes anyinteger therein. For example, a group having from 1-4 atoms could have1, 2, 3, or 4 atoms.

As described herein, compounds of the invention may optionally besubstituted with one or more substituents, such as those illustratedgenerally herein, or as exemplified by particular classes, subclasses,and species of the invention. It will be appreciated that the phrase“optionally substituted” is used interchangeably with the phrase“substituted or unsubstituted.” In general, the term “substituted”,whether preceded by the term “optionally” or not, refers to thereplacement of hydrogen radicals in a given structure with the radicalof a specified substituent. Unless otherwise indicated, an optionallysubstituted group may have a substituent at each substitutable positionof the group, and when more than one position in any given structure maybe substituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds.

The term “stable”, as used herein, refers to compounds that are notsubstantially altered when subjected to conditions to allow for theirproduction, detection, recovery, purification, and use for one or moreof the purposes disclosed herein. In some embodiments, a stable compoundor chemically feasible compound is one that is not substantially alteredwhen kept at a temperature of 40° C. or less, in the absence of moistureor other chemically reactive conditions, for at least a week.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched), branched, or cyclic, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation that has a single point ofattachment to the rest of the molecule.

Unless otherwise specified, aliphatic groups contain 1-20 aliphaticcarbon atoms. In some embodiments, aliphatic groups contain 1-10aliphatic carbon atoms. In other embodiments, aliphatic groups contain1-8 aliphatic carbon atoms. In still other embodiments, aliphatic groupscontain 1-6 aliphatic carbon atoms, and in yet other embodimentsaliphatic groups contain 1-4 aliphatic carbon atoms. Aliphatic groupsmay be linear or branched, substituted or unsubstituted alkyl, alkenyl,or alkynyl groups. Specific examples include, but are not limited to,methyl, ethyl, isopropyl, n-propyl, sec-butyl, vinyl, n-butenyl,ethynyl, and tert-butyl.

The term “cycloaliphatic” (or “carbocycle” or “carbocyclyl”) refers to amonocyclic C3-C8 hydrocarbon or bicyclic C8-C12 hydrocarbon that iscompletely saturated or that contains one or more units of unsaturation,but which is not aromatic, that has a single point of attachment to therest of the molecule wherein any individual ring in said bicyclic ringsystem has 3-7 members. Examples of cycloaliphatic groups include, butare not limited to, cycloalkyl and cycloalkenyl groups. Specificexamples include, but are not limited to, cyclohexyl, cyclopropenyl, andcyclobutyl.

The term “heterocycle”, “heterocyclyl”, or “heterocyclic” as used hereinmeans non-aromatic, monocyclic, bicyclic, or tricyclic ring systems inwhich one or more ring members are an independently selected heteroatom.In some embodiments, the “heterocycle”, “heterocyclyl”, or“heterocyclic” group has three to fourteen ring members in which one ormore ring members is a heteroatom independently selected from oxygen,sulfur, nitrogen, or phosphorus, and each ring in the system contains 3to 7 ring members.

Examples of heterocycles include, but are not limited to,3-1H-benzimidazol-2-one, 3-(1-alkyl)-benzimidazol-2-one,2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothiophenyl,3-tetrahydrothiophenyl, 2-morpholino, 3-morpholino, 4-morpholino,2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl,2-pyrrolidinyl, 3-pyrrolidinyl, 1-tetrahydropiperazinyl,2-tetrahydropiperazinyl, 3-tetrahydropiperazinyl, 1-piperidinyl,2-piperidinyl, 3-piperidinyl, 1-pyrazolinyl, 3-pyrazolinyl,4-pyrazolinyl, 5-pyrazolinyl, 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-piperidinyl, 2-thiazolidinyl, 3-thiazolidinyl,4-thiazolidinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl,5-imidazolidinyl, indolinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, benzothiolane, benzodithiane, and1,3-dihydro-imidazol-2-one.

Cyclic groups, (e.g. cycloaliphatic and heterocycles), can be linearlyfused, bridged, or spirocyclic.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon (including, any oxidized form of nitrogen,sulfur, phosphorus, or silicon; the quaternized form of any basicnitrogen or; a substitutable nitrogen of a heterocyclic ring, forexample N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) orNR⁺ (as in N-substituted pyrrolidinyl)).

The term “unsaturated”, as used herein, means that a moiety has one ormore units of unsaturation. As would be known by one of skill in theart, unsaturated groups can be partially saturated or fully unsaturated.Examples of partially unsaturated groups include, but are not limitedto, butene, cyclohexene, and tetrahydropyridine. Examples of fullyunsaturated groups include, but are not limited to, phenyl,cyclooctatetraene, pyridyl, and thienyl.

The term “alkoxy”, or “thioalkyl”, as used herein, refers to an alkylgroup, as previously defined, attached through an oxygen (“alkoxy”) orsulfur (“thioalkyl”) atom.

The terms “haloalkyl”, “haloalkenyl”, “haloaliphatic”, and “haloalkoxy”mean alkyl, alkenyl or alkoxy, as the case may be, substituted with oneor more halogen atoms. This term includes perfluorinated alkyl groups,such as —CF₃ and —CF₂CF₃.

The terms “halogen”, “halo”, and “hal” mean F, Cl, Br, or I.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic,bicyclic, and tricyclic ring systems having a total of five to fourteenring members, wherein at least one ring in the system is aromatic andwherein each ring in the system contains 3 to 7 ring members. The term“aryl” may be used interchangeably with the term “aryl ring”.

The term “heteroaryl”, used alone or as part of a larger moiety as in“heteroaralkyl” or “heteroarylalkoxy”, refers to monocyclic, bicyclic,and tricyclic ring systems having a total of five to fourteen ringmembers, wherein at least one ring in the system is aromatic, at leastone ring in the system contains one or more heteroatoms, and whereineach ring in the system contains 3 to 7 ring members. The term“heteroaryl” may be used interchangeably with the term “heteroaryl ring”or the term “heteroaromatic”. Examples of heteroaryl rings include, butare not limited to, 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl,4-imidazolyl, 5-imidazolyl, benzimidazolyl, 3-isoxazolyl, 4-isoxazolyl,5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl,2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl),2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl),triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl,benzofuryl, benzothiophenyl, indolyl (e.g., 2-indolyl), pyrazolyl (e.g.,2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, purinyl, pyrazinyl,1,3,5-triazinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl,4-quinolinyl), and isoquinolinyl (e.g., 1-isoquinolinyl,3-isoquinolinyl, or 4-isoquinolinyl).

The term “protecting group” and “protective group” as used herein, areinterchangeable and refer to an agent used to temporarily block one ormore desired functional groups in a compound with multiple reactivesites. In certain embodiments, a protecting group has one or more, orpreferably all, of the following characteristics: a) is addedselectively to a functional group in good yield to give a protectedsubstrate that is b) stable to reactions occurring at one or more of theother reactive sites; and c) is selectively removable in good yield byreagents that do not attack the regenerated, deprotected functionalgroup. As would be understood by one skilled in the art, in some cases,the reagents do not attack other reactive groups in the compound. Inother cases, the reagents may also react with other reactive groups inthe compound. Examples of protecting groups are detailed in Greene, T.W., Wuts, P. G in “Protective Groups in Organic Synthesis”, ThirdEdition, John Wiley & Sons, New York: 1999 (and other editions of thebook), the entire contents of which are hereby incorporated byreference. The term “nitrogen protecting group”, as used herein, refersto an agent used to temporarily block one or more desired nitrogenreactive sites in a multifunctional compound. Preferred nitrogenprotecting groups also possess the characteristics exemplified for aprotecting group above, and certain exemplary nitrogen protecting groupsare also detailed in Chapter 7 in Greene and Wuts, “Protective Groups inOrganic Synthesis”, Third Edition, John Wiley & Sons, New York: 1999,the entire contents of which are hereby incorporated by reference.

The term “cross-coupling”, as used herein, refers to a reaction in whicha carbon-nitrogen bond is formed with the aid of a metal catalyst orbase. Examples of reactions that form carbon-nitrogen bonds, e.g.,Chan-Lam couplings, Buchwald couplings and Buchwald Hartwig couplings,are described herein.

Buchwald or Buchwald-Hartwig coupling conditions involve the use of apalladium catalyst, a base, and a suitable solvent. Examples of suitablecatalysts include, but are not limited to, (Pd[P(o-Tolyl)₃]₂),Pd₂(dba)₃, Pd(dba)₂, and [2-(2-aminoethyl)phenyl]-chloro-palladium;tBuXPhos. Suitable solvents include, but are not limited to, toluene,dioxane, and THF. Optional bases include NaOtBu or LiHMDS. Sometimes abidentate phosphine ligand, e.g., BINAP or DPPF, can also be included.

Chan-Lam coupling conditions involve the use of copper acetate, a base,and a suitable solvent. Suitable bases include, but are not limited to,triethylamine and pyridine. Suitable solvents include, but are notlimited to, dichloromethane and toluene.

Chan-Lam, Buchwald, and Buchwald-Hartwig coupling conditions are knownto one skilled in the art and are described in more detail in a varietyof references.

Unless otherwise indicated, a substituent connected by a bond drawn fromthe center of a ring means that the substituent can be bonded to anyposition in the ring. In example i below, for instance, J¹ can be bondedto any position on the pyridyl ring. For bicyclic rings, a bond drawnthrough both rings indicates that the substituent can be bonded from anyposition of the bicyclic ring. In example ii below, for instance, J¹ canbe bonded to the 5-membered ring (on the nitrogen atom, for instance),and to the 6-membered ring.

In some embodiments, a methylene unit of an alkyl or aliphatic chain isoptionally replaced with another atom or group. Examples of such atomsor groups include, but are not limited to, —NR—, —O—, —C(O)—,—C(═N—CN)—, —C(═NR)—, —C(═NOR)—, —S—, —SO—, and —SO₂—. These atoms orgroups can be combined to form larger groups. Examples of such largergroups include, but are not limited to, —OC(O)—, —C(O)CO—, —CO₂—,—C(O)NR—, —C(═N—CN), —NRC(O)—, —NRC(O)O—, —SO₂NR—, —NRSO₂—, —NRC(O)NR—,—OC(O)NR—, and —NRSO₂NR—, wherein R is defined herein.

Unless otherwise indicated, the optional replacements form a chemicallystable compound. Optional replacements can occur both within the chainand/or at either end of the chain; i.e. both at the point of attachmentand/or also at the terminal end. Two optional replacements can also beadjacent to each other within a chain so long as it results in achemically stable compound. The optional replacements can alsocompletely replace all of the carbon atoms in a chain. For example, a C₃aliphatic can be optionally replaced by —NR—, —C(O)—, and —NR— to form—NRC(O)NR— (a urea).

Unless otherwise indicated, if the replacement occurs at the terminalend, the replacement atom is bound to an H on the terminal end. Forexample, if a methylene unit of —CH₂CH₂CH₃ was optionally replaced with—O—, the resulting compound could be —OCH₂CH₃, —CH₂OCH₃, or —CH₂CH₂OH.In another example, if a methylene unit of —CH₂CH₂CH₃ was optionallyreplaced with —NH—, the resulting compound could be —NHCH₂CH₃,—CH₂NHCH₃, or —CH₂CH₂NH₂.

Unless otherwise indicated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, geometric,conformational, and rotational) forms of the structure. For example, theR and S configurations for each asymmetric center, (Z) and (E) doublebond isomers, and (Z) and (E) conformational isomers are included inthis invention. As would be understood to one skilled in the art, asubstituent con freely rotate around any rotatable bonds. For example, asubstituent drawn as

also represents

Therefore, single stereochemical isomers as well as enantiomeric,diastereomeric, geometric, conformational, and rotational mixtures ofthe present compounds are within the scope of the invention.

Unless otherwise indicated, all tautomeric forms of the compounds of theinvention are within the scope of the invention.

Additionally, unless otherwise indicated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures except for the replacement of hydrogen by deuteriumor tritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enrichedcarbon are within the scope of this invention. Such compounds areuseful, for example, as analytical tools or probes in biological assays.

Pharmaceutically Acceptable Salts, Solvates, Chlatrates, Prodrugs andOther Derivatives

The compounds described herein can exist in free form, or, whereappropriate, as salts. Those salts that are pharmaceutically acceptableare of particular interest since they are useful in administering thecompounds described below for medical purposes. Salts that are notpharmaceutically acceptable are useful in manufacturing processes, forisolation and purification purposes, and in some instances, for use inseparating stereoisomeric forms of the compounds of the invention orintermediates thereof

As used herein, the term “pharmaceutically acceptable salt” refers tosalts of a compound which are, within the scope of sound medicaljudgment, suitable for use in contact with the tissues of humans andlower animals without undue side effects, such as, toxicity, irritation,allergic response and the like, and are commensurate with a reasonablebenefit/risk ratio.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge et al., describe pharmaceutically acceptable saltsin detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporatedherein by reference. Pharmaceutically acceptable salts of the compoundsdescribed herein include those derived from suitable inorganic andorganic acids and bases. These salts can be prepared in situ during thefinal isolation and purification of the compounds.

Where the compound described herein contains a basic group, or asufficiently basic bioisostere, acid addition salts can be preparedby 1) reacting the purified compound in its free-base form with asuitable organic or inorganic acid and 2) isolating the salt thusformed. In practice, acid addition salts, e.g., compound I-34 describedherein, might be a more convenient form for use and use of the saltamounts to use of the free basic form.

Examples of pharmaceutically acceptable, non-toxic acid addition saltsare salts of an amino group formed with inorganic acids such ashydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid andperchloric acid or with organic acids such as acetic acid, oxalic acid,maleic acid, tartaric acid, citric acid, succinic acid or malonic acidor by using other methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, glycolate, gluconate, glycolate,hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate,lauryl sulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, salicylate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like.

Where the compound described herein contains a carboxy group or asufficiently acidic bioisostere, base addition salts can be preparedby 1) reacting the purified compound in its acid form with a suitableorganic or inorganic base and 2) isolating the salt thus formed. Inpractice, use of the base addition salt might be more convenient and useof the salt form inherently amounts to use of the free acid form. Saltsderived from appropriate bases include alkali metal (e.g., sodium,lithium, and potassium), alkaline earth metal (e.g., magnesium andcalcium), ammonium and N⁺(C₁₋₄alkyl)₄ salts. This invention alsoenvisions the quaternization of any basic nitrogen-containing groups ofthe compounds disclosed herein. Water or oil-soluble or dispersibleproducts may be obtained by such quaternization.

Basic addition salts include pharmaceutically acceptable metal and aminesalts. Suitable metal salts include the sodium, potassium, calcium,barium, zinc, magnesium, and aluminium. The sodium and potassium saltsare usually preferred. Further pharmaceutically acceptable saltsinclude, when appropriate, nontoxic ammonium, quaternary ammonium, andamine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and arylsulfonate. Suitable inorganic base addition salts are prepared frommetal bases, which include sodium hydride, sodium hydroxide, potassiumhydroxide, calcium hydroxide, aluminium hydroxide, lithium hydroxide,magnesium hydroxide, zinc hydroxide and the like. Suitable amine baseaddition salts are prepared from amines which are frequently used inmedicinal chemistry because of their low toxicity and acceptability formedical use. Ammonia, ethylenediamine, N-methyl-glucamine, lysine,arginine, ornithine, choline, N, N′-dibenzylethylenediamine,chloroprocaine, dietanolamine, procaine, N-benzylphenethylamine,diethylamine, piperazine, tris(hydroxymethyl)-aminomethane,tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine,dehydroabietylamine, N-ethylpiperidine, benzylamine,tetramethylammonium, tetraethylammonium, methylamine, dimethylamine,trimethylamine, ethylamine, basic amino acids, dicyclohexylamine and thelike are examples of suitable base addition salts.

Other acids and bases, while not in themselves pharmaceuticallyacceptable, may be employed in the preparation of salts useful asintermediates in obtaining the compounds described herein and theirpharmaceutically acceptable acid or base addition salts.

It should be understood that this invention includesmixtures/combinations of different pharmaceutically acceptable salts andalso mixtures/combinations of compounds in free form andpharmaceutically acceptable salts.

The compounds described herein can also exist as pharmaceuticallyacceptable solvates (e.g., hydrates) and clathrates. As used herein, theterm “pharmaceutically acceptable solvate,” is a solvate formed from theassociation of one or more pharmaceutically acceptable solvent moleculesto one of the compounds described herein. The term solvate includeshydrates (e.g., hemihydrate, monohydrate, dihydrate, trihydrate,tetrahydrate, and the like).

As used herein, the term “hydrate” means a compound described herein ora salt thereof that further includes a stoichiometric ornon-stoichiometric amount of water bound by non-covalent intermolecularforces.

As used herein, the term “clathrate” means a compound described hereinor a salt thereof in the form of a crystal lattice that contains spaces(e.g., channels) that have a guest molecule (e.g., a solvent or water)trapped within.

In addition to the compounds described herein, pharmaceuticallyacceptable derivatives or prodrugs of these compounds may also beemployed in compositions to treat or prevent the herein identifieddisorders.

A “pharmaceutically acceptable derivative or prodrug” includes anypharmaceutically acceptable ester, salt of an ester, or other derivativeor salt thereof of a compound described herein which, uponadministration to a recipient, is capable of providing, either directlyor indirectly, a compound described herein or an inhibitorily activemetabolite or residue thereof. Particularly favoured derivatives orprodrugs are those that increase the bioavailability of the compoundswhen such compounds are administered to a patient (e.g., by allowing anorally administered compound to be more readily absorbed into the blood)or which enhance delivery of the parent compound to a biologicalcompartment (e.g., the brain or lymphatic system) relative to the parentspecies.

As used herein and unless otherwise indicated, the term “prodrug” meansa derivative of a compound that can hydrolyze, oxidize, or otherwisereact under biological conditions (in vitro or in vivo) to provide acompound described herein. Prodrugs may become active upon such reactionunder biological conditions, or they may have activity in theirunreacted forms. Examples of prodrugs contemplated in this inventioninclude, but are not limited to, analogs or derivatives of compounds ofthe invention that comprise biohydrolyzable moieties such asbiohydrolyzable amides, biohydrolyzable esters, biohydrolyzablecarbamates, biohydrolyzable carbonates, biohydrolyzable ureides, andbiohydrolyzable phosphate analogues. Other examples of prodrugs includederivatives of compounds described herein that comprise —NO, —NO₂, —ONO,or —ONO₂ moieties. Prodrugs can typically be prepared using well-knownmethods, such as those described by BURGER'S MEDICINAL CHEMISTRY ANDDRUG DISCOVERY (1995) 172-178, 949-982 (Manfred E. Wolff ed., 5th ed).

ABBREVIATIONS

The following abbreviations are used:

-   DMSO dimethyl sulfoxide-   NMR nuclear magnetic resonance-   HPLC high performance liquid chromatography-   LCMS liquid chromatography-mass spectrometry-   Rt retention time-   DCM dichloromethane-   THF tetrahydrofuran-   LiHMDS lithium bis(trimethyl)amide-   PS-DEAM polymer bound diethanolamine-   DMEM Dulbecco's Modified Eagle Media

Compound Uses

One aspect of this invention provides compounds or compositions that areinhibitors of indoleamine 2,3-dioxygenase (IDO), or pharmaceuticallyacceptable salts thereof, and thus are useful for treating or lesseningthe severity of a disease, condition, or disorder in a patient, whereinIDO is implicated in the disease, condition, or disorder.

The terms, “disease”, “disorder”, and “condition” may be usedinterchangeably here to refer to an IDO mediated medical or pathologicalcondition.

The term “IDO mediated condition”, as used herein, means any diseasestate or other deleterious condition in which IDO is known to play arole. The term “IDO mediated condition” or “disease” also means thosediseases or conditions that are alleviated by treatment with an IDOinhibitor. Such conditions include cancer and sepsis.

As used herein, the terms “subject” and “patient” are usedinterchangeably. The terms “subject” and “patient” refer to an animal,and more specifically a human. In one embodiment, the subject is anon-human animal such as a rat or dog. In a preferred embodiment, thesubject is a human.

Another aspect of this invention provides compounds that are useful forthe treatment of diseases, disorders, and conditions, e.g, viraldisease, pneumonia, bacteremia, trauma, tuberculosis, parasitic disease,neuroinflammation, schizophrenia, depression, neurodegenerative disease,and pain.

Examples of neurodegenerative diseases include, without limitation,Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis(ALS), Dementia, Multiple Sclerosis, and Huntington's disease.

Examples of viral diseases include, without limitation, HumanImmunodeficiency Virus (HIV), Hepatitis A-D, Human Papilloma Virus(HPV), and Herpes, including Herpes Simplex I and II, as well as theEpstein Barr Virus.

Another aspect of this invention provides compounds that are useful forthe treatment of diseases, disorders, and conditions, e.g., sepsis.

Another aspect of this invention provides compounds that are useful forthe treatment of diseases, disorders, and conditions characterized byexcessive or abnormal cell proliferation. Such diseases include aproliferative or hyperproliferative disease. Examples of proliferativeand hyperproliferative diseases include, without limitation, cancer andmyeloproliferative disorders.

In some embodiments, said compounds are selected from the groupconsisting of a compound of formula I. The term “cancer” includes, butis not limited to the following cancers. Oral: head and neck, includingbuccal cavity, lip, tongue, mouth, pharynx; Cardiac: sarcoma(angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma,rhabdomyoma, fibroma, lipoma and teratoma; Lung: Non-small cell lungcarcinoma including adenocarcinoma (acinar, bronchioloalveolar carcinoma[nonmucinous, mucinous, mixed], papillary, solid adenocarcionoma, clearcell, mucinous [colloid] adenocarcinoma, mucinous cystadenocarcinoma,signet ring, well-differentiated fetal), bronchioalveolar, squamous cellcarcinoma (basaloid, clear cell, papillary, small cell), large cell(undifferentiated) carcinoma (giant cell, basaloid, clear cell, largecell [with rhabdoid phenotype], large cell neuroendocrine carcinoma[LCNEC], combined LCNEC); small cell lung cancer including small cell(oat cell) carcinoma, combined small cell; adenoid cystic carcinoma;hamartoma; lymphoma; neuroendocrine/carcinoid; sarcoma.Gastrointestinal: esophagus (squamous cell carcinoma, larynx,adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma,leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma,glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel or smallintestines (adenocarcinoma, lymphoma, carcinoid tumors, Karposi'ssarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), largebowel or large intestines (adenocarcinoma, tubular adenoma, villousadenoma, hamartoma, leiomyoma), colon, colon-rectum, colorectal; rectum,Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor[nephroblastoma], lymphoma, leukemia), bladder and urethra (squamouscell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate(adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonalcarcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cellcarcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver:hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma,angiosarcoma, hepatocellular adenoma, hemangioma, biliary passages;Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibroushistiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma(reticulum cell sarcoma), multiple myeloma, malignant giant cell tumorchordoma, osteochronfroma (osteocartilaginous exostoses), benignchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma andgiant cell tumors; Nervous system: skull (osteoma, hemangioma,granuloma, xanthoma, osteitis deformans), meninges (meningioma,meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma,glioma, ependymoma, germinoma [pinealoma], glioblastoma multiform,oligodendroglioma, schwannoma, retinoblastoma, congenital tumors),spinal cord neurofibroma, meningioma, glioma, sarcoma);Female/Gynecological: uterus (endometrial carcinoma), cervix (cervicalcarcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma[serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiedcarcinoma], granulosa-thecal cell tumors, Sertoli-Leydig cell tumors,dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma,intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma),vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma(embryonal rhabdomyosarcoma), fallopian tubes (carcinoma), breast;Hematologic: blood (myeloid leukemia [acute and chronic], acutelymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferativediseases, multiple myeloma, myelodysplastic syndrome), Hodgkin'sdisease, non-Hodgkin's lymphoma [malignant lymphoma] hairy cell;lymphoid disorders; Skin: malignant melanoma, basal cell carcinoma,squamous cell carcinoma, Karposi's sarcoma, keratoacanthoma, molesdysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis,Thyroid gland: papillary thyroid carcinoma, follicular thyroidcarcinoma, undifferentiated thyroid cancer, medullary thyroid carcinoma,multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type2B, familial medullary thyroid cancer, pheochromocytoma, paraganglioma;and Adrenal glands: neuroblastoma.

Thus, the term “cancerous cell” as provided herein, includes a cellafflicted by any one of the above-identified conditions. In someembodiments, the cancer is selected from head and neck, ovarian,melanoma cervical, endometrial, esophageal, or breast cancer.

The term “myeloproliferative disorders”, includes disorders such aspolycythemia vera, thrombocythemia, myeloid metaplasia withmyelofibrosis, hypereosinophilic syndrome, juvenile myelomonocyticleukemia, systemic mast cell disease, and hematopoietic disorders, inparticular, acute-myelogenous leukemia (AML), chronic-myelogenousleukemia (CML), acute-promyelocytic leukemia (APL), and acutelymphocytic leukemia (ALL).

Combination Therapies

Another aspect of this invention is directed towards a method oftreating cancer in a subject in need thereof, comprising administrationof a compound of this invention or a pharmaceutically acceptable saltthereof, and an additional therapeutic agent. In some embodiments, saidmethod comprises the sequential or co-administration of the compound ofthis invention, or a pharmaceutically acceptable salt thereof, and theadditional therapeutic agent. Alternatively, those additional agents maybe administered separately, as part of a multiple dosage regimen, fromthe IDO inhibitor-containing compound or composition. Furthermore, thoseagents may be part of a single dosage form or mixed together with theIDO inhibitor in a single composition.

As used herein, the term “in combination” or “co-administration” can beused interchangeably to refer to the use of more than one therapy (e.g.,one or more therapeutic agents). The use of the term does not restrictthe order in which therapies (e.g., therapeutic agents) are administeredto a subject.

In some embodiments, said additional therapeutic agent is selected froman anti-cancer agent, an anti-proliferative agent, or a chemotherapeuticagent.

In some embodiments, said additional therapeutic agent is selected fromcisplatin (Platinol®), carboplatin (Paraplatin®), oxaliplatin(Eloxatin®), daunomycin (Daunorubicin®, DanuoXome®, Cerubidine®),doxorubicin (Adriamycin®, Rubex®), epirubicin (Ellence®), idarubicin(Idamycin®), valrubicin (Valstar®), mitoxantrone (Novantrone®),paclitaxel (Taxol®), docetaxel (Taxotere®) and cyclophosphamide(Cytoxan®).

In other embodiments, said additional therapeutic agent is selected fromanti-cancer antibody or immunoglobulin therapies or agents including,but not limited to, ipilimumab (Yervoy®, Bristol-Myers Squibb),tremelimumab (Pfizer), antibodies or agents that target programmed deathreceptor 1 [PD-1] or programmed death ligand 1 [PD-L1], e.g., CT-011(Curetech), BMS-936558 (Bristol-Myers Squibb), BMS-936559 (Bristol-MyersSquibb), AMP-224 (Amplimmune/Glaxo-Smithkline), or MGA-271(Macrogenics).

In other embodiments, said additional therapeutic agent is an immuneenhancer such as a vaccine, immune-stimulating antibody, immunoglobulin,agent or adjuvant including, but not limited to, sipuleucel-t(Provenge®, Dendreon Corporation), BMS-663513 (Bristol-Myers Squibb),CP-870893 (Pfizer/VLST), anti-OX40 (AgonOX), or CDX-1127 (CellDex).

Other cancer therapies or anticancer agents that may be used incombination with the inventive agents of the present invention includesurgery, radiotherapy (e.g., gamma-radiation, neutron beam radiotherapy,electron beam radiotherapy, proton therapy, brachytherapy, low-doseradiotherapy, and systemic radioactive isotopes), immune responsemodifiers such as chemokine receptor antagonists, chemokines andcytokines (e.g., interferons, interleukins, tumour necrosis factor(TNF), and GM-CSF)), hyperthermia and cryotherapy, agents to attenuateany adverse effects (e.g. antimetics, steroids, anti-inflammatoryagents), and other approved chemotherapeutic drugs.

A compound of the instant invention may also be useful for treatingcancer in combination with or in addition to any of the followingtherapeutic agents: abarelix (Plenaxis Depot®); aldesleukin (Prokine®);Aldesleukin (Proleukin®); Alemtuzumabb (Campath®); alitretinoin(Panretin®); allopurinol (Zyloprim®); altretamine (Hexalen®); amifostine(Ethyol®); anastrozole (Arimidex®); arsenic trioxide (Trisenox®);asparaginase (Elspar®); azacitidine (Vidaza®); bevacuzimab (Avastin®);bexarotene capsules (Targretin®); bexarotene gel (Targretin®); bleomycin(Blenoxane®); bortezomib (Velcade®); busulfan intravenous (Busulfex®);busulfan oral (Myleran®); calusterone (Methosarb®); capecitabine(Xeloda®); carboplatin (Paraplatin®); carmustine (BCNU®, BiCNU®);carmustine (Gliadel®); carmustine with Polifeprosan 20 Implant (GliadelWafer®); celecoxib (Celebrex®); cetuximab (Erbitux®); chlorambucil(Leukeran®); cisplatin (Platinol®); cladribine (Leustatin®, 2-CdA®);clofarabine (Clolar®); cyclophosphamide (Cytoxan®, Neosar®);cyclophosphamide (Cytoxan Injection®); cyclophosphamide (CytoxanTablet®); cytarabine (Cytosar-U®); cytarabine liposomal (DepoCyt®);dacarbazine (DTIC-Dome®); dactinomycin, actinomycin D (Cosmegen®);Darbepoetin alfa (Aranesp®); daunorubicin liposomal (DanuoXome®);daunorubicin, daunomycin (Daunorubicin®); daunorubicin, daunomycin(Cerubidine®); Denileukin diftitox (Ontak®); dexrazoxane (Zinecard®);docetaxel (Taxotere®); doxorubicin (Adriamycin PFS®); doxorubicin(Adriamycin®, Rubex®); doxorubicin (Adriamycin PFS Injection®);doxorubicin liposomal (Doxil®); dromostanolone propionate(Dromostanolone®); dromostanolone propionate (masterone Injection®);Elliott's B Solution (Elliott's B Solution®); epirubicin (Ellence®);Epoetin alfa (Epogen®); erlotinib (Tarceva®); estramustine (Emcyt®);etoposide phosphate (Etopophos®); etoposide, VP-16 (Vepesid®);exemestane (Aromasin®); Filgrastim (Neupogen®); floxuridine(intraarterial) (FUDR®); fludarabine (Fludara®); fluorouracil, 5-FU(Adrucil®); fulvestrant (Faslodex®); gefitinib (Iressa®); gemcitabine(Gemzar®); gemtuzumab ozogamicin (Mylotarg®); goserelin acetate (ZoladexImplant®); goserelin acetate (Zoladex®); histrelin acetate (HistrelinImplant®); hydroxyurea (Hydrea®); Ibritumomab Tiuxetan (Zevalin®);idarubicin (Idamycin®); ifosfamide (IFEX®); imatinib mesylate(Gleevec®); interferon alfa 2a (Roferon A®); Interferon alfa-2b (IntronA®); irinotecan (Camptosar®); lenalidomide (Revlimid®); letrozole(Femara®); leucovorin (Wellcovorin®, Leucovorin®); Leuprolide Acetate(Eligard®); levamisole (Ergamisol®); lomustine, CCNU (CeeBU®);meclorethamine, nitrogen mustard (Mustargen®); megestrol acetate(Megace®); melphalan, L-PAM (Alkeran®); mercaptopurine, 6-MP(Purinethol®); mesna (Mesnex®); mesna (Mesnex Tabs®); methotrexate(Methotrexate®); methoxsalen (Uvadex®); mitomycin C (Mutamycin®);mitotane (Lysodren®); mitoxantrone (Novantrone®); nandrolonephenpropionate (Durabolin-50®); nelarabine (Arranon); Nofetumomab(Verluma®); Oprelvekin (Neumega®); oxaliplatin (Eloxatin®); paclitaxel(Paxene®); paclitaxel (Taxol®); paclitaxel protein-bound particles(Abraxane®); palifermin (Kepivance®); pamidronate (Aredia®); pegademase(Adagen (Pegademase Bovine)®); pegaspargase (Oncaspar®); Pegfilgrastim(Neulasta®); pemetrexed disodium (Alimta®); pentostatin (Nipent®);pipobroman (Vercyte®); plicamycin, mithramycin (Mithracin®); porfimersodium (Photofrin®); procarbazine (Matulane®); quinacrine (Atabrine®);Rasburicase (Elitek®); Rituximab (Rituxan®); sargramostim (Leukine®);Sargramostim (Prokine®); sorafenib (Nexavar®); streptozocin (Zanosar®);sunitinib maleate (Sutent®); talc (Sclerosol®); tamoxifen (Nolvadex®);temozolomide (Temodar®); teniposide, VM-26 (Vumon®); testolactone(Teslac®); thioguanine, 6-TG (Thioguanine®); thiotepa (Thioplex®);topotecan (Hycamtin®); toremifene (Fareston®); Tositumomab (Bexxar®);Tositumomab/I-131 tositumomab (Bexxar®); Trastuzumab (Herceptin®);tretinoin, ATRA (Vesanoid®); Uracil Mustard (Uracil Mustard Capsules®);valrubicin (Valstar®); vinblastine (Velban®); vincristine (Oncovin®);vinorelbine (Navelbine®); zoledronate (Zometa) and vorinostat(Zolinza®).

For a comprehensive discussion of updated cancer therapies see,http://www.nci.nih.gov/, a list of the FDA approved oncology drugs athttp://www.fda.gov/cder/cancer/druglistframe.htm, and The Merck Manual,Seventeenth Ed. 1999, the entire contents of which are herebyincorporated by reference.

Another aspect of this invention is directed towards a method oftreating sepsis in a subject in need thereof, comprising the sequentialor co-administration of a compound of this invention, or apharmaceutically acceptable salt thereof, and one or more additionaltherapeutic agents. In other embodiments, those additional agents may beadministered separately, as part of a multiple dosage regimen, from theIDO inhibitor-containing compound or composition. Alternatively, thoseagents may be part of a single dosage form or mixed together with theIDO inhibitor in a single composition.

In another aspect of the invention, said one or more additionaltherapeutic agents is selected from an antibiotic, a vasopressor, asteroid, an inotrope, an anti-thrombotic agent, a sedative, opioids, oran anesthetic.

In other embodiments, said one or more additional therapeutic agents isselected from cephalosporins, macrolides, penams, beta-lactamaseinhibitors, aminoglycoside antibiotics, fluoroquinolone antibiotics,glycopeptide antibiotics, penems, monobactams, carbapenmems,nitroimidazole antibiotics, lincosamide antibiotics, vasopressors,positive inotropic agents, steroids, benzodiazepines, phenol,alpha2-adrenergic receptor agonists, GABA-A receptor modulators,anti-thrombotic agents, anesthetics, or opiods.

A compound of the instant invention may also be useful for treatingsepsis along with any of the following therapeutic agents:Alatrofloxacin, Amifloxacin, Balofloxacin, Besifloxacin, Ciprofloxacin,Clinafloxacin, Danofloxacin, Delafloxacin, Difloxacin, Enoxacin,Enrofloxacin, Fleroxacin, Garenoxacin, Gatifloxacin, Gemifloxacin,Grepafloxacin, Levofloxacin, Lomefloxacin, Marbofloxacin, Moxifloxacin,Nadifloxacin, Norfloxacin, Ofloxacin, Orbifloxacin, Pazufloxacin,Pefloxacin, Prulifloxacin, Rufloxacin, Sitafloxacin, Sparfloxacin,Temafloxacin, Tosufloxacin, Trovafloxacin, Vancomycin, Teicoplanin,Telavancin, Bleomycin, Ramoplanin, Decaplanin, Azanidazole,Dimetridazole, Metronidazole, Nimorazole, Ornidazole, Propenidazole,Secnidazole, Tinidazole, Linomycin, Clindamycin, Cefazolin,Cefacetril(e), Cefadroxil, Cefalexin, Cefaloglycin, Cefalonium,Cefaloridin(e), Cefaoltin, Cefapirin, Cefatrizin(e), Cefazedon(e),Cefazaflur, Cefradin(e), Cefroxadin(e), Ceftezol(e), Cefaclor,Cefamandole, Cefminox, Cefonicid, Ceforanide, Cefotiam, Cefprozil,Cefbuperazone, Cefuroxime, Cefuzonam, Cephamycin (Cefoxitin, Cefotetan,Cefmetazole), Carbacephem (Loracarbef), Cefixime, Ceftriaxome,Ceftazidime, Cefoperazone, Cefcapene, Cefdaloxime, Cefdinir, Cefditoren,Cafatamet, Cefmenoxime, Cefodizime, Cefotaxime, Cefpimizole,Cefpiramide, Cefpodoxime, Cefsulodin, Cefteram, Ceftibuten, Ceftiolene,Ceftizoxime, Oxacephem, Cefepime, Cefozopran, Cefpirome, Cefquinome,Ceftobiprole, Ceftaroline fosamil, Amoxicillin, Ampicillin, Epicillin,Carbenicillin, e.g., Carindacillin, Ticarcillin, Temocillin, Azlocillin,Piperacillin, Mezlocillin, Mecillinam, Sulbenicillin, Benylpenicillin,Clometocillin, Benzathine benylpenecillin, Procaine benylpenecillin,Azidocillin, Penamecillin, Phenoxymethylpenecillin, Propicillin,Benzathine phenoxymthylpenecillin, Pheneticillin, Cloxacillin,Oxacillin, Meticillin, Nafcillin, Faropenem, Aztreonam, Tigemonam,Carumonam, Nocardicin A, Biapenem, Ertapenem, Antipseudomonal,Panipenem, Penam, Clavam, Azithromycin, Clarithromycin, Dirithromycin,Erythromycin, Kitasamycin, Midecamycin, Roxithromycin, Troleandomycin,Ansamycin, Carbomycin, Cethromycin, Oleandomycin, Solithromycin,Spiramycin, Telithromycin, Tylosin, Amikacin, Arbekcacin, Gentamicin,Kanamycin, Neomycin, Netilmicin, Paromycin, Rhodostreptomycin,Streptomycin, Tobramycin, Apramycin, Norepinephrine, Epinephrine,Phenylepinephrine, Dopamine, Vasopressin, Berberine, Calcium, Omecamtiv,Dobutamine, Dopexamine, Isoprenaline, Phenylepinephrine, Dogoxin,Prostaglandins, Enoximone, Milrinone, Amrinone, Theophylline, Digitalis,Glucagon, Hydrocortisone, Cortisone, Fluorocortisone, Heparin, Diazepam,Lorazepam, Midazolam, Propofol, Dexmedetomidine, Etomidate, Fentanyl,Hydromorphone, Morphine, Meperidine, Remifentanil, or Ketamine.

Other examples of agents the compounds of this invention may also becombined with, or used in addition to, include, without limitation:treatments for Alzheimer's Disease such as Aricept® and Excelon®;treatments for Parkinson's Disease such as L-DOPA/carbidopa, entacapone,ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, andamantadine; agents for treating Multiple Sclerosis (MS) such as betainterferon (e.g., Avonex® and Rebir), Copaxone®, and mitoxantrone;treatments for asthma such as albuterol and Singulair®; agents fortreating schizophrenia such as zyprexa, risperdal, seroquel, andhaloperidol; anti-inflammatory agents such as corticosteroids, TNFblockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine;immunomodulatory agents such as cyclosporin, tacrolimus, rapamycin,mycophenolate mofetil, interferons, corticosteroids, cyclophophamide,azathioprine, and sulfasalazine; neurotrophic factors such asacetylcholinesterase inhibitors, MAO inhibitors, interferons,anti-convulsants, ion channel blockers, riluzole, and anti-Parkinsonianagents; agents for treating blood disorders such as corticosteroids,anti-leukemic agents, and growth factors; and agents for treatingimmunodeficiency disorders such as gamma globulin.

Depending upon the particular IDO-mediated conditions to be treated orprevented, additional drugs, which are normally administered to treat orprevent that condition, may be administered together with the compoundsof this invention.

Compositions for Administration into a Subject

The IDO inhibitors or pharmaceutical salts thereof may be formulatedinto pharmaceutical compositions for administration to animals orhumans. These pharmaceutical compositions, which comprise an amount ofthe IDO inhibitor effective to treat or prevent an IDO mediatedcondition and a pharmaceutically acceptable carrier thereof, are anotherembodiment of the present invention.

The exact amount of compound required for treatment will vary fromsubject to subject, depending on the species, age, and general conditionof the subject, the severity of the infection, the particular agent, itsmode of administration, and the like. The compounds of the invention arepreferably formulated in dosage unit form for ease of administration anduniformity of dosage. The expression “dosage unit form” as used hereinrefers to a physically discrete unit of agent appropriate for thepatient to be treated. It will be understood, however, that the totaldaily usage of the compounds and compositions of the present inventionwill be decided by the attending physician within the scope of soundmedical judgment. The specific effective dose level for any particularpatient or organism will depend upon a variety of factors including thedisorder being treated and the severity of the disorder; the activity ofthe specific compound employed; the specific composition employed; theage, body weight, general health, sex and diet of the patient; the timeof administration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed, andlike factors well known in the medical arts.

In some embodiments, these compositions optionally further comprise oneor more additional therapeutic agents. For example, chemotherapeuticagents or other anti-proliferative agents may be combined with thecompounds of this invention to treat proliferative diseases and cancer.Examples of known agents with which these compositions can be combinedare listed above under the “Combination Therapies” section and alsothroughout the specification. Some embodiments provide a simultaneous,separate or sequential use of a combined preparation.

Modes of Administration and Dosage Forms

The pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention may be administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 100mg/kg and preferably from about 1 mg/kg to about 50 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polethylene glycols and the like.

The active compounds can also be in microencapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, eardrops, and eye drops are also contemplated asbeing within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

The compositions of the present invention may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes, but is not limited to, subcutaneous,intravenous, intramuscular, intra-articular, intra-synovial,intrasternal, intrathecal, intrahepatic, intralesional and intracranialinjection or infusion techniques. Preferably, the compositions areadministered orally, intraperitoneally or intravenously.

Sterile injectable forms of the compositions of this invention may beaqueous or oleaginous suspension. These suspensions may be formulatedaccording to techniques known in the art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose, any bland fixed oilmay be employed including synthetic mono- or di-glycerides. Fatty acids,such as oleic acid and its glyceride derivatives are useful in thepreparation of injectables, as are natural pharmaceutically-acceptableoils, such as olive oil or castor oil, especially in theirpolyoxyethylated versions. These oil solutions or suspensions may alsocontain a long-chain alcohol diluent or dispersant, such ascarboxymethyl cellulose or similar dispersing agents which are commonlyused in the formulation of pharmaceutically acceptable dosage formsincluding emulsions and suspensions. Other commonly used surfactants,such as Tweens, Spans and other emulsifying agents or bioavailabilityenhancers which are commonly used in the manufacture of pharmaceuticallyacceptable solid, liquid, or other dosage forms may also be used for thepurposes of formulation.

The pharmaceutical compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers commonly used include, but arenot limited to, lactose and corn starch. Lubricating agents, such asmagnesium stearate, are also typically added. For oral administration ina capsule form, useful diluents include lactose and dried cornstarch.When aqueous suspensions are required for oral use, the activeingredient is combined with emulsifying and suspending agents. Ifdesired, certain sweetening, flavoring or coloring agents may also beadded.

Alternatively, the pharmaceutical compositions of this invention may beadministered in the form of suppositories for rectal administration.These can be prepared by mixing the agent with a suitable non-irritatingexcipient that is solid at room temperature but liquid at rectaltemperature and therefore will melt in the rectum to release the drug.Such materials include, but are not limited to, cocoa butter, beeswaxand polyethylene glycols.

The pharmaceutical compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, the pharmaceutical compositions may beformulated in a suitable ointment containing the active componentsuspended or dissolved in one or more carriers. Carriers for topicaladministration of the compounds of this invention include, but are notlimited to, mineral oil, liquid petrolatum, white petrolatum, propyleneglycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax andwater. Alternatively, the pharmaceutical compositions can be formulatedin a suitable lotion or cream containing the active components suspendedor dissolved in one or more pharmaceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated asmicronized suspensions in isotonic, pH adjusted sterile saline, or,preferably, as solutions in isotonic, pH adjusted sterile saline, eitherwith or without a preservative such as benzylalkonium chloride.Alternatively, for ophthalmic uses, the pharmaceutical compositions maybe formulated in an ointment such as petrolatum.

The pharmaceutical compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

The amount of IDO inhibitor that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated, the particular mode of administration. Preferably, thecompositions should be formulated so that a dosage of between 0.01-100mg/kg body weight/day of the inhibitor can be administered to a patientreceiving these compositions.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of inhibitor will also depend upon the particular compound in thecomposition.

Biological Samples

As inhibitors of IDO activity, the compounds and compositions of thisinvention are also useful in biological samples. One aspect of theinvention relates to inhibiting IDO activity in a biological sample,which method comprises contacting said biological sample with a compoundof formula I-A or a composition comprising said compound. The term“biological sample”, as used herein, means an in vitro or an ex vivosample, including, without limitation, cell cultures or extractsthereof; biopsied material obtained from a mammal or extracts thereof;and blood, saliva, urine, feces, semen, tears, or other body fluids orextracts thereof

Inhibition of IDO activity in a biological sample is useful for avariety of purposes that are known to one of skill in the art. Examplesof such purposes include, but are not limited to, cancer treatment.

Study of IDO

Another aspect of this invention relates to the study of IDO inbiological and pathological phenomena; the study of intracellular signaltransduction pathways mediated by IDO; and the comparative evaluation ofnew IDO inhibitors. Examples of such uses include, but are not limitedto, biological assays such as enzyme assays and cell-based assays.

The activity of the compounds as IDO inhibitors may be assayed in vitroor in vivo. In vitro assays include assays that quantitate the abilityof the inhibitor to bind to IDO and may be determined by measuring theproduction of kynurenine. Detailed conditions for assaying a compoundutilized in this invention as an inhibitor of IDO is set forth in theExamples below.

Another aspect of the invention provides a method for modulating enzymeactivity by contacting a compound of formula I-A with IDO.

Methods of Treatment

In one aspect, the present invention provides a method for treating orlessening the severity of a disease, condition, or disorder where IDO isimplicated in the disease state. In another aspect, the presentinvention provides a method for treating or lessening the severity of anIDO mediated disease, condition, or disorder where inhibition ofenzymatic activity is implicated in the treatment of the disease. Inanother aspect, this invention provides a method for treating orlessening the severity of a disease, condition, or disorder withcompounds that inhibit enzymatic activity by binding to IDO. Anotheraspect provides a method for treating or lessening the severity of anIDO mediated disease, condition, or disorder by inhibiting enzymaticactivity of IDO with an IDO inhibitor.

In another aspect, the present invention provides a method forinhibiting IDO activity in a patient comprising administering to thepatient a compound or composition of the present invention. In anotherembodiment, the present invention provides a method for inhibiting IDOactivity in a biological sample comprising administering a compound orcomposition of the present invention.

One aspect of the invention relates to a method of inhibiting IDOactivity in a patient, which method comprises administering to thepatient a compound described herein, or a composition comprising saidcompound. In some embodiments, the method is used to treat or prevent acondition selected from a proliferative or hyperproliferative disease,e.g., cancer. In another embodiment, the method is used to treat orprevent sepsis.

Another aspect of the invention provides a method of treating,preventing, or lessening the severity of a disease or condition of apatient selected from cancer, proliferative disorder, viral disease,sepsis, pneumonia, bacteremia, trauma, tuberculosis, parasitic disease,neuroinflammation, schizophrenia, depression, neurodegenerative disease,and pain, by administering a compound or composition of the presentinvention. In another embodiment, the method comprises the additionalstep of administering to said patient an additional therapeutic agentselected from a chemotherapeutic or anti-proliferative agent, ananti-inflammatory agent, an immunomodulatory or immunosuppressive agent,a neurotrophic factor, an agent for treating cardiovascular disease, anagent for treating destructive bone disorders, an anti-viral agent, anagent for treating blood disorders, or an agent for treatingimmunodeficiency disorders, wherein said additional therapeutic agent isappropriate for the disease being treated; and said additionaltherapeutic agent is administered together with the composition as asingle dosage form or separately from said composition as part of amultiple dosage form.

Experimental Materials and Methods

All commercially available solvents and reagents were used as received.¹H-NMR spectra were recorded at 500 MHz using a Bruker Ascend 500instrument. Mass spec. samples were analyzed on a MicroMass QuattroMicro mass spectrometer operated in single MS mode with electrosprayionization. Where stated, purification of final compounds were executedusing FractionLynx™ HPLC mass directed purification or ISCO CombiFlash®Companion.

As used herein, the term “Rt(min)” refers to the HPLC retention time, inminutes, associated with the compound. Unless otherwise indicated, theHPLC methods utilized to obtain the reported retention times are asdescribed below:

HPLC Method

Instrument: Waters Acquity UPLC-MS

Column: Waters UPLC BEH C8 1.7 μm, 2.1×50 mm with Vanguard BEH C8 1.7μm, 2.1×5 mm guard column

Column temperature: 45 C

Mobile Phase A: 10 mM ammonium formate in water:acetonitrile 95:5, pH 9

Mobile Phase B: acetonitrile

Gradient: initial: 2% B, 0-1.15 min: 2% B to 98% B, 1.15-1.35 min: holdat 98% B, 1.35-1.40 min: 98% B to 2% B, 1.40-1.50 min: hold at 2% B

Flow rate: 1.0 mL/minute

Detection: 210-400 nm

Mass spectrometer: Waters SQD with electrospray ionization operating inpositive and negative ion mode.

SCHEMES AND EXAMPLES

The compounds of the disclosure may be prepared in light of thespecification using steps generally known to those of ordinary skill inthe art. Those compounds may be analyzed by known methods, including butnot limited to LCMS (liquid chromatography mass spectrometry) and NMR(nuclear magnetic resonance), described above. The generic schemes andexamples, described below, illustrate how to prepare the compounds ofthe present disclosure. The examples are for the purpose of illustrationonly and are not to be construed as limiting the scope of the inventionin any way.

Scheme 1 shows one general route to compounds I-A. An appropriatearomatic amine 1 was diazotised with sodium nitrite to generate anintermediate diazonium species, which was further reacted with aminoacetonitrile to generate a triazine 2. A one pot thermal ring closurefollowed by a Dimroth rearrangement provided the aminotriazole I-A.

Example 1 Preparation of5-((2H-1,2,3-triazol-4-yl)amino)-2-chlorobenzonitrile (compound I-44)Step 1: 2-Chloro-5-(3-(cyanomethyl)triaz-1-en-1-yl)benzonitrile

5-amino-2-chloro-benzonitrile (800 mg, 5.243 mmol) was dissolved inhydrochloric acid (12.06 mL of 2 M, 24.12 mmol) and diluted with water(16 mL) and cooled to 0° C. Sodium nitrite (362 mg, 167 μL, 5.24 mmol)was added and the reaction was stirred at 0° C. for 20 min and then asolution of 2-aminoacetonitrile monohydrochloride (485 mg, 5.24 mmol) inwater (6 mL) was slowly added. The mixture was stirred for 10 min at 0°C. and sodium acetate (6.04 g, 73.61 mmol) was then added and themixture allowed to warm to room temperature and stirred for 1 h. Theprecipitate was collected by filtration and washed with water to affordthe title compound 2a as a tan colored solid. MS m/z: 220.1 (M+H)⁺.

Step 2: 5-((2H-1,2,3-Triazol-4-yl)amino)-2-chlorobenzonitrile

2-Chloro-5-(3-(cyanomethyl)triaz-1-en-1-yl)benzonitrile 2a (1.15 g, 5.24mmol) was dissolved in EtOH (23 mL) and heated to reflux for 4 h. Themixture was allowed to cool to room temperature and then concentrated.The material was triturated with DCM to produce a cream solid which waspurified by ISCO (30-40% EtOAc in hexanes) to afford the title compoundI-44 as a yellow solid (231 mg, 20%). ¹H NMR (500 MHz, d6-DMSO) δ 14.45(1H, s), 9.33 (1H, s), 7.80 (1H, s), 7.65-7.39 (3H, m). MS m/z: 220.1(M+H)⁺.

The following aminotriazoles were synthesised using a similar procedureas outlined for Compound I-44: Compounds I-1, I-2, I-5, I-16, I-18,I-19, I-25, I-26, and I-37.

Scheme 2 shows an alternative route to compounds I-A. An appropriatearomatic azide 3 was cyclised with ethyl 2-cyanoacetate to provide thesubstituted 1,2,3-triazole 4. Basic ester hydrolysis and decarboxylationsequence provided the aminotriazole I-A.

Example 2 Preparation ofN-(3-chloro-4-fluorophenyl)-2H-1,2,3-triazol-4-amine (compound I-13)Step 1: Ethyl5-amino-1-(3-chloro-4-fluorophenyl)-1H-1,2,3-triazole-4-carboxylate

To a solution of ethyl 2-cyanoacetate (857.2 mg, 0.81 mL, 7.58 mmol) inEtOH (13 mL) was added sodium ethoxide (4.00 mL of 2 M in EtOH, 8.00mmol). 4-azido-2-chloro-1-fluoro-benzene (1.0 g, 5.83 mmol) was addeddropwise followed by additional EtOH (5 mL). The reaction was stirredfor 1 h and then concentrated to afford the title compound 4a as ayellow solid (1.5 g, 88%). MS m/z: 254.8 (M−H)⁺.

Step 2: N-(3-Chloro-4-fluorophenyl)-2H-1,2,3-triazol-4-amine

Ethyl5-amino-1-(3-chloro-4-fluorophenyl)-1H-1,2,3-triazole-4-carboxylate 4a(120.0 mg, 0.4 mmol) was suspended in aqueous NaOH (4.00 mL of 2 M, 8.00mmol) and the solution heated to reflux and stirred for 3 h. Thesolution was allowed to cool and acidified with 1M HCl and thenextracted into EtOAc and the organic layer concentrated. The residue wasdissolved in DMSO (2 mL) and heated to 110° C. for 3 h. The mixture wasallowed to cool and purified by FractionLynx to afford the titlecompound I-13 as a white solid (56.8 mg, 64%). ¹H NMR (500 MHz, d6-DMSO)δ 8.74 (1H, brs), 7.48-7.50 (1H, m), 7.31 (1H, s), 7.20-7.24 (1H, m),7.10-7.13 (1H, m). MS m/z: 212.9 (M+H)⁺.

The following aminotriazoles were synthesised using a similar procedureas outlined for Compound I-13: Compounds I-3, I-11, I-14, I-24, I-29,and I-30.

Scheme 3 shows an alternative route to compounds I-A. A suitablyprotected aminotriazole 5 was reacted with a suitably activated aromaticpartner 6 (Y═Br, Cl, BOR₂; R is defined herein) to produce the coupledprotected aminotriazole 7. Subsequent functional group manipulations, asrequired, and a triazole deprotection step provided the aminotriazoleI-A.

Example 3 Preparation of Intermediate Compound 5 Method 1:1-Benzyl-1H-1,2,3-triazol-5-amine

A suspension of 5-amino-1-benzyl-triazole-4-carboxylic acid (5.00 g,22.91 mmol) in N,N-dimethylaniline (23 mL) was heated to reflux andstirred for 20 min and then allowed to cool and stirred overnight atroom temperature. The reaction was cooled in an ice bath and the solidprecipitate was filtered, washed with hexanes, and air dried to affordthe title compound 5a as an off white solid (1.90 g, 48%). ¹H NMR (500MHz, d6-DMSO) δ 7.33-7.35 (1H, m), 7.27-7.30 (1H, m), 7.18-7.21 (2H, m),6.81 (1H, s), 5.58 (2H, brs), 5.35 (2H, s). MS m/z: 175.0 (M+H)⁺.

Method 2: 2-((2-(Trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-amine5b and 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,3-triazol-4-amine 5cStep 1: 5-Nitro-2-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,3-triazoleand 4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,3-triazole

To a solution of 4-nitro-1H-triazole (5.00 g, 43.84 mmol) in THF (230mL), cooled to 0° C., was added sodium hydride (2.28 g, 56.99 mmol)portionwise over 30 min. The mixture was stirred for a further 30 minand then 2-(chloromethoxy)ethyl-trimethyl-silane (7.67 g, 8.15 mL, 46.03mmol) was added dropwise. The reaction was allowed to warm to roomtemperature and stirred for 2 h, then re-cooled to 0° C. and quenchedwith water. The mixture was extracted with EtOAc and the organics washedwith brine, dried (MgSO₄) and concentrated. The residue was purified bycolumn chromatography eluting with 5% EtOAc in hexanes to afford4-nitro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole (6.18 g,56%) and 4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,3-triazoleas an off white solid (3.52 g, 33%).

Step 2a: 2-((2-(Trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-amine

To prepare a compound of 5b, a mixture of4-nitro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole (3.80 g,15.55 mmol) and palladium on carbon [wet, Degussa] (1.66 g, 1.56 mmol)in MeOH (66 mL) was degassed several times using vacuum/nitrogen cyclesand then vacuum/hydrogen cycles and left under a hydrogen atmosphere for18 h. The mixture was filtered through celite, the celite washed withmethanol, and concentrated to afford2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-amine 5b as acolorless oil (3.12 g, 94%). ¹H NMR (500 MHz, d6-DMSO) δ 7.03 (1H, s),5.40 (2H, s), 5.13 (2H, s), 3.58 (2H, dd), 0.85 (2H, dd), 0.01 (9H, s).

Step 2b: 1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-1,2,3-triazol-4-amine

To prepare a compound of 5c, a mixture of4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,3-triazole (1.2 g,4.91 mmol) and palladium on carbon [wet, Degussa] (523 mg, 0.49 mmol) inMeOH (21 mL) was degassed several times using vacuum/nitrogen cycles andthen vacuum/hydrogen cycles and left under a hydrogen atmosphere for 18h. The mixture was filtered through celite, the celite washed withmethanol, and concentrated to afford1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,3-triazol-4-amine 5c as anoff white solid (1.04 g, 98%). ¹H NMR (500 MHz, d6-DMSO) δ 7.20 (1H, s),5.51 (2H, s), 4.78 (2H, s), 3.53 (2H, dd), 0.86 (2H, dd), 0.00 (9H, s).

Example 4 Preparation of(2-((2H-1,2,3-triazol-4-yl)amino)-5-chlorophenyl)methanol (compound I-9)Step 1: [2-[(3-Benzyltriazol-4-yl)amino]-5-chloro-phenyl]methanol

Preparation of 2-((1-benzyl-1H-1,2,3-triazol-5-yl)amino)-5-chlorobenzoicacid

A solution of 1-benzyl-1H-1,2,3-triazol-5-amine 5a (1.00 g, 5.74 mmol)in THF (10 mL) was cooled to −78° C. LiHMDS (14.35 mL of 1M in THF,14.35 mmol) was added dropwise. Upon complete addition4-chloro-2-fluoro-benzoic acid (1.00 g, 5.74 mmol) in THF (5 mL) wasadded and the mixture stirred at −78° C. for 10 min and allowed to warmto room temperature and then heated at 100° C. for 20 h. The mixture wasthen treated with water (10 mL) and concentrated. The residue waspartitioned between EtOAc and 1M HCl and the organic layer dried(Na₂SO₄) and concentrated to afford2-((1-benzyl-1H-1,2,3-triazol-5-yl)amino)-5-chlorobenzoic acid (1.89 g,quant). MS m/z: 329.1 (M+H)⁺.

Preparation of [2-[(3-benzyltriazol-4-yl)amino]-5-chloro-phenyl]methanol

A solution of 2-((1-benzyl-1H-1,2,3-triazol-5-yl)amino)-5-chlorobenzoicacid (965 mg, 2.94 mmol) in THF (7.5 mL) was treated with borane (14.68mL of 1M in THF, 14.68 mmol). The reaction was stirred for 21 h beforeadding additional borane (4.4 mL of 1M in THF, 4.40 mmol) and stirringfor an additional 1 h. The reaction was quenched with water andconcentrated. The residue was then stirred in 3M Methanolic HCl for 1 hand then concentrated. The residue was partitioned between EtOAc andwater and the organic layer dried (MgSO₄) and concentrated to afford thetitle compound 7a (895 mg, 97%). MS m/z: 315.1 (M+H)⁺.

Step 2:-(2-((2H-1,2,3-Triazol-4-yl)amino)-5-chlorophenyl)methanol

A solution of [2-[(3-benzyltriazol-4-yl)amino]-5-chloro-phenyl]methanol7a (300 mg, 0.95 mmol) in MeOH (5 mL) was treated with formic acid (1.00mL, 26.51 mmol). The mixture was degassed by vacuum/nitrogen cyclesbefore the addition of palladium on carbon (507.1 mg, 0.48 mmol). Themixture was stirred under an argon atmosphere at room temperature for 18h and then filtered through celite and concentrated. The material waspurified by FractionLynx to afford the title compound I-9 as a solid(90.0 mg, 40%). 1H NMR (500 MHz, DMSO) δ 14.20 (1H, s), 7.85-7.80 (1H,s), 7.60 (1H, s), 7.51 (1H, s), 7.31 (1H, d), 7.19 (1H, d), 4.55 (2H,s). MS m/z: 223.1 (M−H)⁺.

Example 5 Preparation ofN-(2-(aminomethyl)-4-chlorophenyl)-2H-1,2,3-triazol-4-amine (compoundI-34) Step 1:N-[2-(Aminomethyl)-4-chloro-phenyl]-3-benzyl-triazol-4-amine

Preparation of 2-[(3-benzyltriazol-4-yl)amino]-5-chloro-benzonitrile

1-Benzyl-1H-1,2,3-triazol-5-amine 5a (1.00 g, 5.74 mmol) and5-chloro-2-fluoro-benzonitrile (892.9 mg, 5.74 mmol) were combined inTHF (6 mL) and cooled to −78° C. LiHMDS (6.31 mL of 1 M, 6.31 mmol) wasadded dropwise and the reaction stirred for 5 min and then allowed towarm to room temperature and subsequently heated at 60° C. for 1 h. Themixture was quenched water and then evaporated and the residuepartitioned between EtOAc and 1M HCl, the organic layer separated andconcentrated. Trituration of the residue in EtOAc and hexanes afforded2-[(3-benzyltriazol-4-yl)amino]-5-chloro-benzonitrile as a brown solid(1.06 g, 60%). MS m/z: 310.1 (M+H)⁺.

Preparation ofN-[2-(aminomethyl)-4-chloro-phenyl]-3-benzyl-triazol-4-amine

A solution of 2-[(3-benzyltriazol-4-yl)amino]-5-chloro-benzonitrile (439mg, 1.42 mmol) in THF (3 mL) was treated with borane (6.00 mL of 1 M inTHF, 6.00 mmol) and then stirred at room temperature for 1 h. Themixture was then treated with water (5 mL) and concentrated beforepartitioning between EtOAc and water. The organic layer was concentratedand the resulting residue was stirred in 3M methanolic HCl for 1 h andthen concentrated. The residue was partitioned between EtOAc and waterand the organic layer separated and concentrated to afford the titlecompound 7b (439 mg, 99%). MS m/z: 314.2 (M+H)⁺.

Step 2:-N-(2-(Aminomethyl)-4-chlorophenyl)-2H-1,2,3-triazol-4-amine

A solution ofN-[2-(aminomethyl)-4-chloro-phenyl]-3-benzyl-triazol-4-amine 7b (439 mg,1.40 mmol) in dry MeOH (18 mL) and EtOAc (18 mL) was treated withdibromozinc (126.0 mg, 0.56 mmol). The degassed mixture was then treatedwith 10% palladium on carbon (297.8 mg, 0.28 mmol) before affixing ahydrogen balloon. The mixture was stirred at room temperature for 2 hbefore filtering through celite and concentrating. The material waspurified on an ISCO (0-100% MeOH in DCM) and the freebase was stirred in4N HCl in dioxane for 30 min before evaporating to afford the titlecompound I-34 (mono hydrochloride salt) as a solid (291 mg, 80%). ¹H NMR(500 MHz, DMSO-d6) δ 8.52 (1H, s) 8.47 (3H, m), 7.63 (1H, d), 7.53 (s,1H), 7.48 (1H, d), 7.31 (1H, d) 4.12 (2H, q). MS m/z: 224.1 (M+H)⁺.

Example 6 Preparation ofN-(24(2H-1,2,3-triazol-4-yl)amino)-5-chlorobenzyl)acetamide (compoundI-20) Step 1:N-[[2-[(3-Benzyltriazol-4-yl)amino]-5-chloro-phenyl]methyl]acetamide

A solution ofN-[2-(aminomethyl)-4-chloro-phenyl]-3-benzyl-triazol-4-amine (asdescribed in Example 5) (512 mg, 1.63 mmol) and triethylamine (495 mg,682 μL, 4.90 mmol) in THF (15 mL) was treated with acetyl chloride(128.1 mg, 116 μL, 1.63 mmol) and the mixture stirred at roomtemperature for 75 min. The reaction was then quenched with water andconcentrated. The residue was partitioned between EtOAc and saturatedaqueous sodium hydrogen carbonate and the organic layer was separatedand concentrated. Purification by column chromatography (0-100% EtOAc inhexanes) afforded the title compound 7c (105 mg, 18%). MS m/z: 356.2(M+H)⁺.

Step 2: N-(2-((2H-1,2,3-Triazol-4-yl)amino)-5-chlorobenzyl)acetamide

N-[[2-[(3-Benzyltriazol-4-yl)amino]-5-chloro-phenyl]methyl]acetamide 7c(105 mg, 0.30 mmol) was dissolved in MeOH (5 mL) and treated with formicacid (367 mg, 301 μL, 7.97 mmol). The mixture was degassed byvacuum/nitrogen cycles before the addition of palladium on carbon (157mg, 0.15 mmol). An argon balloon was affixed and the mixture was left tostir for 15 h before filtering through celite and concentrating. Thematerial was purified by FractionLynx to afford the title compound I-20(0.5 TFA salt) as a solid (28.2 mg, 29%). ¹H NMR (500 MHz, DMSO) δ 8.53(1H, t), 8.32-8.36 (1H, m), 7.61 (1H, d), 7.44 (1H, s), 7.15-7.25 (2H,m), 4.28 (2H, d), 1.93 (3H, s). MS m/z: 266.1 (M+H)⁺.

The following aminotriazoles were synthesised using a similar procedureas outlined for Compound I-20: Compound I-21.

Example 7 Preparation ofN-(4-fluoro-2-methylphenyl)-2H-1,2,3-triazol-4-amine (compound I-36)Step 1: 1-Benzyl-N-(4-fluoro-2-methylphenyl)-1H-1,2,3-triazol-5-amine

To a mixture of 1-benzyl-1H-1,2,3-triazol-5-amine (235 mg, 1.35 mmol),chloro[2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl)]palladium(II) (9.23 mg, 0.013 mmol),ditert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (5.73 mg,0.013 mmol) and sodium 2-methylpropan-2-olate (272 mg, 2.83 mmol) undernitrogen was added 1-bromo-4-fluoro-2-methyl-benzene (319 mg, 213.2 μL,1.69 mmol) and t-BuOH (10 mL) and the reaction heated to reflux for 2 h.The reaction was allowed to cool and concentrated and diluted withwater, saturated aqueous ammonium chloride and EtOAc. The aqueous wasfurther extracted with EtOAc and the combined organics dried (Na₂SO₄)and concentrated. The material was purified by ISCO (0-100% EtOAc inhexanes) to afford the title compound 7d as an oil (247 mg, 65%). MSm/z: 283.2 (M+H)⁺.

Step 2: N-(4-Fluoro-2-methylphenyl)-2H-1,2,3-triazol-4-amine

A solution of1-benzyl-N-(4-fluoro-2-methylphenyl)-1H-1,2,3-triazol-5-amine 7d (247mg, 0.87 mmol) in EtOAc (8 mL) and MeOH (8 mL) was degassed byvacuum/nitrogen cycles (×3) and treated with palladium on carbon [wet,Degussa] (186 mg, 0.18 mmol). The mixture was degassed byvacuum/hydrogen cycles (×3) and left under a hydrogen atmosphere for 3h. Reaction was filtered through celite and concentrated and thematerial purified by FractionLynx to afford the title compound I-36 as asolid (0.5 TFA salt) (121 mg, 55%). ¹H NMR (500 MHz, d6-DMSO) δ7.48-7.76 (2H, m), 7.39 (1H, s), 6.99 (1H, dd), 6.91 (1H, dd), 2.25 (3H,t). MS m/z: 193.1 (M+H)⁺.

The following aminotriazoles were synthesised using a similar procedureas outlined for compound I-36: compounds I-17 and I-23. However, bromidecoupling partners were synthesised using the following methodologies.

Synthesis of 2-(2-bromo-5-chlorophenyl)-N-methylethanesulfonamide

To a solution of methylamine (1.18 mL of 2 M, 2.34 mmol) andtriethylamine (477.2 mg, 657 μL, 4.72 mmol) in DCM (20 mL) was added2-(2-bromo-5-chloro-phenyl)ethanesulfonyl chloride (500 mg, 1.57 mmol)and the mixture stirred at room temperature for 2 h. A further quantityof methylamine (2 mL) was added and the reaction stirred at roomtemperature for 18 h. The reaction was diluted with DCM and saturatedaqueous sodium chloride and the organic layer was concentrated to affordthe title compound 6a as an off white solid (465 mg, 95%). ¹H NMR (500MHz, d6-DMSO) δ 7.40 (1H, d), 7.16-7.28 (1H, m), 7.04 (1H, dd), 4.51(1H, brs), 3.18-3.33 (2H, m), 3.05-3.18 (2H, m), 2.75 (3H, s).

Synthesis of tert-butyl 2-bromo-5-chlorobenzyl(methyl)carbamate

To a solution of 1-(2-bromo-5-chloro-phenyl)-N-methyl-methanamine (1.00g, 4.26 mmol) in THF (10 mL) was added triethylamine (517.8 mg, 713.2μL, 5.12 mmol) and tert-butoxycarbonyl tert-butyl carbonate (977.1 mg,1.029 mL, 4.48 mmol) and the solution stirred at room temperature for 2h. The reaction was diluted with EtOAc and water and the organic washedwith sequentially with 1N HCl, saturated aqueous sodium hydrogencarbonate, and brine. The organic was dried (Na₂SO₄) and concentrated toafford the title compound 6b as an oil (1.42 g, 100%). ¹H NMR (500 MHz,d6-DMSO) δ 7.65 (1H, d), 7.29-7.31 (1H, m), 7.18 (1H, s), 4.44 (2H, s),2.87 (3H, s), 1.41 (9H, s).

Example 8 Preparation of N-(3-fluorophenyl)-2H-1,2,3-triazol-4-amine(compound I-45) Step 1:N-(3-Fluorophenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-amine

To a mixture of2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-amine 5b (100mg, 0.47 mmol),chloro[2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl)]palladium(II) (3.21 mg, 0.0047 mmol),di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (1.98 mg,0.0047 mmol) and sodium-tert-butoxide (94.2 mg, 0.98 mmol) under anitrogen atmosphere was added 1-bromo-3-fluoro-benzene (81.6 mg, 0.47mmol) and t-BuOH (4.5 mL). The reaction was heated to reflux for 2 h andallowed to cool and concentrated. The residue was diluted with EtOAc andwater and the organic dried (MgSO₄) and concentrated. The material waspurified by ISCO (0-20% EtOAc in hexanes) to afford the title compound7e as a colorless oil (51 mg, 35%). MS m/z: 309.2 (M+H)⁺.

Step 2: N-(3-Fluorophenyl)-2H-1,2,3-triazol-4-amine

ToN-(3-fluorophenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,3-triazol-5-amine7e (50 mg, 0.16 mmol) was added ethane-1,2-diamine (50 mg, 55.6 μL, 0.83mmol) and tetrabutylammonium fluoride (424 mg, 478 μL, 1.62 mmol) andthe mixture was heated to 90° C. in a microwave for 2 h. The mixture wasdiluted with EtOAc and water and the organic was washed with water,brine and then dried (MgSO₄) and concentrated. Material was purified byFractionlynx to afford the title compound I-45 as a white solid (10 mg,35%). ¹H NMR (500 MHz, d6-DMSO) δ 14.19 (1H, s), 9.02 (1H, s), 7.39 (1H,d), 7.17-7.27 (2H, m), 6.99-7.06 (1H, m), 6.52-6.61 (1H, m). MS m/z:179.1 (M+H)⁺.

The following aminotriazoles were synthesised using a similar procedureas outlined for compound I-45: compounds I-4, I-6, I-7, I-8, I-10, I-12,I-15, I-19, I-27, I-38, I-39, I-40, I-41, I-42, I-46, I-47, and I-48.However, bromide coupling partners for compounds I-4, I-6, I-46, I-47,and I-48 were synthesised using the following methodologies.

Synthesis of 1-bromo-4-chloro-2-(methoxymethyl)benzene

To a solution of (2-bromo-5-chloro-phenyl)methanol (3.16 g, 14.25 mmol)in THF (50 mL) at room temperature was added sodium hydride (684 mg,17.10 mmol). The mixture was stirred for 30 min and then iodomethane(3.04 g, 1.33 mL, 21.38 mmol) was added and the reaction stirredovernight. The mixture was diluted with saturated aqueous ammoniumchloride and EtOAc and the organic washed with water, then brine, anddried (Na₂SO₄) and concentrated to afford the title compound 6c as anoil (3.36 g, quant). ¹H NMR (500 MHz, CDCl₃) δ 7.40-7.48 (2H, m),7.11-7.14 (1H, m), 4.47 (2H, s), 3.48 (3H, s).

Synthesis of 1-Bromo-4-chloro-2-(2-methoxyethyl)benzene

Step 1: 2-(2-bromo-5-chlorophenyl)ethanol

A solution of 2-(2-bromo-5-chloro-phenyl)acetic acid (1.00 g, 4.01 mmol)in THF (16 mL) was cooled to 0° C. Borane-tetrahydrofuran complex (6.0mL, 62.69 mmol) was added and the solution allowed to warm to roomtemperature and stirred for 3 h. Another portion ofborane-tetrahydrofuran complex (6.0 mL, 62.69 mmol) was added and thereaction stirred overnight. The reaction was cooled to 0° C. andquenched by the careful addition of cold water. The aqueous wasextracted with EtOAc and the organic layer washed with 2M HCl, dried(Na₂SO₄), and concentrated. The material was dissolved in DCM andPS-DEAM (1 g) was added and stirred overnight. The resin was filteredwashing with DCM and concentrated to afford2-(2-bromo-5-chlorophenyl)ethanol as an oil (944 mg, quant). ¹H NMR (500MHz, CDCl₃) δ 7.40 (1H, d), 7.30 (1H, s), 7.00-7.03 (1H, m), 3.80-3.84(2H, m), 2.91-2.94 (2H, m).

Step 2: 1-Bromo-4-chloro-2-(2-methoxyethyl)benzene

A solution of 2-(2-bromo-5-chlorophenyl)ethanol (1.00 g, 4.03 mmol) inTHF (50 mL) was cooled to −78° C. and LiHMDS (4.24 mL of 1 M, 4.24 mmol)was added the mixture stirred for 40 min. Iodomethane (601 mg, 263.7 μL,4.24 mmol) was added and the solution allowed to warm to roomtemperature and stirred for 2 h. The reaction was re-cooled to −78° C.and another portion of LiHMDS (4.24 mL of 1 M, 4.24 mmol) was added,stirred for 40 min, and another portion of iodomethane (601 mg, 263.7μL, 4.24 mmol) was added. After stirring at room temperature for 2 h thereaction was cooled to 0° C. and quenched with water. The aqueous wasextracted with EtOAc and the organics was with brine, dried (Na₂SO₄),and concentrated. Material was purified using an ISCO (0-100%EtOAc/hexanes) to afford the title compound 6d as a yellow oil (428 mg,32%). ¹H NMR (500 MHz, CDCl₃) δ 7.39 (1H, d), 7.20 (1H, s), 7.00 (1H,d), 3.54 (2H, t), 3.30 (3H, s), 2.93 (2H, t).

Synthesis of 4-(2-bromo-5-chlorophenethyl)morpholine

Step 1: 2-bromo-5-chlorophenethyl methanesulfonate

A solution of 2-(2-bromo-5-chloro-phenyl)ethanol (1.65 g, 7.00 mmol) [asprepared in preparation 6] and triethylamine (922 mg, 1.27 mL, 9.11mmol) in DCM (20 mL) was cooled to 0° C. and methanesulfonyl chloride(883 mg, 597 μL, 7.71 mmol) was added. The mixture was stirred for 2 hand then diluted with DCM and washed sequentially with water and brine,the organic layer dried (MgSO₄) and concentrated to afford2-bromo-5-chlorophenethyl methanesulfonate as a yellow solid (2.11 g,96%). ¹H NMR (500 MHz, d6-DMSO) δ 7.67 (1H, d), 7.55 (1H, s), 7.32 (1H,d), 4.44 (2H, t), 3.13-3.36 (5H, m).

Step 2: 4-(2-bromo-5-chlorophenethyl)morpholine

A solution of 2-(2-bromo-5-chloro-phenyl)ethyl methanesulfonate (261 mg,0.83 mmol) and morpholine (218 mg, 218 μL, 2.50 mmol) in toluene (4 mL)was heated to reflux and stirred overnight. The mixture was allowed tocool to room temperature and diluted with EtOAc and washed sequentiallywith water and brine, the organic layer dried (MgSO₄) and concentratedto afford the title compound 6e as a pale yellow oil (228 mg, 90%). ¹HNMR (500 MHz, d6-DMSO) δ 7.61 (1H, d), 7.50 (1H, s), 7.24 (1H, D),3.57-3.59 (4H, m), 2.86 (2H, t), 2.50-2.52 (4H, m), (1×CH₂ masked underDMSO peak). MS m/z: 305.9 (M+H)⁺.

The bromide coupling partner for I-47 was prepared in an analogousfashion to the bromide coupling partner for compound I-46, with theexception that the starting material is ethyl3-(2-bromo-5-chloro-phenyl)propanoate.

Synthesis of 1-(2-(2-bromo-5-chlorophenoxy)ethyl)-4-methylpiperazine

Step 1: 1-bromo-2-(2-bromoethoxy)-4-chlorobenzene

To a suspension of 2-bromo-5-chloro-phenol (2.58 g, 12.44 mmol) in water(8 mL) was added sodium hydroxide (995 mg, 24.88 mmol) and the solutionheated to reflux for 1 h and then allowed to cool to room temperature.1,2-dibromoethane (4.67 g, 24.88 mmol) was added and the mixture heatedat reflux for 25 h. The solution was allowed to cool to room temperatureand partitioned between EtAOc and water. The aqueous was washed withsaturated sodium hydrogen carbonate, water and brine and then dried(MgSO₄) and concentrated. Material was purified using an ISCO (0-5%EtOAc/hexanes) to afford 1-bromo-2-(2-bromoethoxy)-4-chlorobenzene as awhite solid (1.30 g, 33%). ¹H NMR (500 MHz, d6-DMSO) δ 7.62 (1H, d),7.26 (1H, s), 7.02 (1H, d), 4.46 (2H, t), 3.83 (2H, t).

Step 2: 1-(2-(2-bromo-5-chlorophenoxy)ethyl)-4-methylpiperazine

A solution of 1-bromo-2-(2-bromoethoxy)-4-chlorobenzene (200.0 mg, 0.64mmol) and 1-methylpiperazine (191.1 mg, 1.91 mmol) in toluene (3.0 mL)was heated to reflux for 30 min. The mixture was allowed to cool to roomtemperature and diluted with EtOAc. The organics were washed with waterand brine and then dried (MgSO₄) and concentrated to afford the titlecompound 6f as a pale yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 7.59 (1H,d), 7.26 (1H, s), 6.97 (1H, d), 4.19 (2H, t), 2.72 (2H, t), 2.31 (4H,brs), 2.14 (3H, s).

Example 9 Preparation of6-chloro-N-(2H-1,2,3-triazol-4-yl)pyridin-3-amine (compound I-22) Step1:6-Chloro-N-(2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-yl)pyridin-3-amine

A slurry of2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-amine 5b (130mg, 0.61 mmol), (6-chloro-3-pyridyl)boronic acid (191 mg, 1.21 mmol),diacetoxycopper (220 mg, 1.21 mmol) and triethylamine (123 mg, 169.0 μL,1.21 mmol) in DCM (22 mL) was added 4A molecular sieves and the mixturestirred overnight at room temperature. The mixture was filtered throughcelite and treated with aqueous ammonia solution. The organic layer wasseparated and washed with brine, dried (Na₂SO₄), and concentrated toafford the title compound 7f as an oil. MS m/z: 326.1 (M+H)⁺.

Step 2: 6-Chloro-N-(2H-1,2,3-triazol-4-yl)pyridin-3-amine

A mixture of6-chloro-N-(2-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,3-triazol-5-yl)pyridin-3-amine7f (175 mg, 0.54 mmol), ethane-1,2-diamine (161 mg, 180 μL, 2.69 mmol)and tetrabutylammonium fluoride (2.69 mL of 2 M in THF, 5.37 mmol) washeated at 90° C. in a microwave for 80 min. The mixture was concentratedand purified by FractionLynx to afford the title compound I-22 as an offwhite solid (0.25 TFA salt) (32.5 mg, 25%). ¹H NMR (500 MHz, d6-DMSO) δ14.28 (1H, s), 9.19 (1H, s), 8.38 (1H, s), 7.82-7.83 (1H, m), 7.42 (1H,s), 7.34-7.36 (1H, m). MS m/z: 196.0 (M+H)⁺.

The following aminotriazoles were synthesised using a similar procedureas outlined for compound I-22: compound I-43. The boronic acid couplingpartner was synthesised using the following methodology.

Synthesis of (4-chloro-2-(2-(N,N-dimethylsulfamoyl)ethyl)phenyl)boronicacid

Step 1: 2-(2-bromo-5-chlorophenyl)-N,N-dimethylethanesulfonamide

To a solution of dimethylamine (1.91 mL of 2 M, 3.82 mmol) andtriethylamine (386.7 mg, 532.6 μL, 3.82 mmol) in THF (8.1 mL) at roomtemperature was added 2-(2-bromo-5-chloro-phenyl)ethanesulfonyl chloride(405.0 mg, 1.27 mmol) and the mixture stirred for 10 min. The mixturewas diluted with EtOAc and washed subsequently with water and brine, theorganic layer dried (MgSO₄) and concentrated to afford2-(2-bromo-5-chlorophenyl)-N,N-dimethylethanesulfonamide as a whitesolid (413 mg, 99%). ¹H NMR (500 MHz, d6-DMSO) δ 7.66 (1H, d), 7.60 (1H,s), 7.30 (1H, d), 3.31-3.34 (2H, m), 3.08-3.12 (2H, m).

Step 2:2-(5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N,N-dimethylethanesulfonamide

A mixture of 2-(2-bromo-5-chlorophenyl)-N,N-dimethylethanesulfonamide(413 mg, 1.26 mmol), potassium acetate (521 mg, 5.31 mmol) andbis(pinacolato)diboron (369 mg, 1.45 mmol) in dioxane (11.8 mL) wasdegassed via vacuum/nitrogen cycles (×3) and then1-cyclopenta-1,4-dienyl-diphenyl-phosphane-dichloromethane-dichloropalladium-iron(82.6 mg, 0.10 mmol) was added and the reaction heated at 95° C.overnight. The reaction was allowed to cool to room temperature anddiluted with EtOAc and water. The organic was washed with brine, dried(MgSO₄) and concentrated. Material was purified by ISCO (0-20%EtOAc/hexanes) to afford2-(5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N,N-dimethylethanesulfonamide as a white solid (357 mg, 76%). MS m/z: 374.2 (M+H)⁺.

Step 3: (4-chloro-2-(2-(N,N-dimethylsulfamoyl)ethyl)phenyl)boronic acid

To a solution of2-(5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N,N-dimethylethanesulfonamide(357 mg, 0.96 mmol) in THF (14 mL) and water (3.5 mL) was addedsodium(meta)periodate (284 mg, 2.87 mmol) and the mixture stirred atroom temperature for 15 min. HCl (1.91 mL of 2 M, 3.82 mmol) was addedand the mixture stirred for a further 4.5 h. The reaction was extractedwith EtOAc and the organic washed sequentially with water and brine,dried (MgSO₄) and concentrated to afford the title 6f compound as acream sticky solid (265 mg, 95%). MS m/z: 292.1 (M+H)⁺.

Example 10 Preparation of3-(2-((2H-1,2,3-triazol-4-yl)amino)-5-chlorobenzyl)cyclobutanecarboxylicacid (compound I-28) Step 1:Ethyl-3-[(2-bromo-5-chloro-phenyl)methylene]cyclobutanecarboxylate

Preparation of (2-Bromo-5-chloro-phenyl)methyl-triphenyl-phosphoniumbromide

To a solution of 1-bromo-2-(bromomethyl)-4-chloro-benzene (3.00 g, 10.55mmol) in THF (50 mL) was added triphenylphosphane (4.15 g, 15.82 mmol)and the solution was stirred at room temperature for 20 h. During thistime a white solid precipitated. Reaction mixture was filtered to give awhite solid, which was slurried with ether and filtered to afford thetitle compound as a white solid (3.74 g, 65%). MS m/z: 467.0 (M+H)⁺.

Preparation ofEthyl-3-[(2-bromo-5-chlorophenyl)methylene]cyclobutanecarboxylate

Sodium hydride (85 mg, 2.11 mmol) was added in small portions to asolution of (2-bromo-5-chloro-phenyl)methyl-triphenyl-phosphoniumbromide (1.05 g, 1.92 mmol) in THF (8 mL) and the solution stirred atroom temperature for 2 h. A solution of ethyl3-oxocyclobutanecarboxylate (273 mg, 1.92 mmol) in THF (1 mL) was addedand the solution stirred at room temperature for 24 h. Water and EtOAcwas added and the organic washed with brine, dried (MgSO₄) andconcentrated. Material was purified by flash column chromatography onsilica gel eluting with 5% ether in hexanes to afford the title compound6g as a semi solid/oil (63 mg, 10%). ¹H NMR (500 MHz, CDCl₃) δ 7.37-7.40(1H, d), 7.15 (1H, s), 7.91-7.95 (1H, d), 6.32 (1H, s), 4.11 (2H, q),3.00-3.27 (5H, m), 1.18 (3H, t).

Step2:-3-(2-((1-Benzyl-1H-1,2,3-triazol-5-yl)amino)-5-chlorobenzylidene)cyclobutanecarboxylic acid

To a mixture of 1-benzyl-1H-1,2,3-triazol-5-amine 5a (43.2 mg, 0.25mmol),chloro[2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl)]palladium(II) (1.71 mg, 0.0025 mmol),2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (1.1 mg, 0.0025mmol) and sodium tert-butoxide (50 mg, 0.52 mmol) under a nitrogenatmosphere was addedethyl-3-[(2-bromo-5-chloro-phenyl)methylene]cyclobutanecarboxylate 6g(90 mg, 0.27 mmol) and t-BuOH (2 mL). The mixture was degassed byvacuum/nitrogen cycles (3×) and then heated to reflux for 1 h. Themixture was concentrated and the resulting residue was treated withwater, acidified with 5% citric acid, and extracted with EtOAc (3×). Thecombined organic layers were washed with brine, dried (MgSO₄), andconcentrated to afford the title compound 7g as a brown viscous oil (75mg, 76%). MS m/z: 395.2 (M+H)⁺.

Step4:-3-(2-((2H-1,2,3-Triazol-4-yl)amino)-5-chlorobenzyl)cyclobutanecarboxylicacid

To a solution of3-(2-((1-benzyl-1H-1,2,3-triazol-5-yl)amino)-5-chlorobenzylidene)cyclobutanecarboxylicacid 7 g (75 mg, 0.19 mmol) and dibromozinc (17.1 mg, 0.076 mmol) inEtOAc (2 mL) and MeOH (2 mL) was added 10% Pd on C [wet Degussa type](40 mg, 0.038 mmol). The reaction was then flushed with hydrogen viavacuum/hydrogen cycles (3×) and the mixture stirred under a hydrogenatmosphere for 2 h at room temperature. Additional 10% Pd on C [wetDegussa type] (40 mg, 0.038 mmol) was added and stirred under hydrogenfor a further 1 h. Acetic acid (23 mg, 21.60 μL, 0.38 mmol) was thenadded and mixture stirred under hydrogen overnight. Additional aceticacid (22 mg, 21.60 μL, 0.38 mmol) was added and stirred under hydrogenatmosphere again overnight. The reaction mixture was then filteredthrough celite washing through with methanol. The filtrate wasconcentrated and the material purified by FractionLynx to afford thetitle compound I-28 as a white solid (1.5 TFA salt) (4.0 mg, 3.9%yield). ¹H NMR (500 MHz, d6-DMSO) δ 7.78 (1H, brs), 7.59 (1H, brs), 7.46(1H, brs), 7.10-7.12 (1H, m), 7.06 (1H, d), 2.87-2.94 (1H, m), 2.72 (2H,d), 2.50-2.55 (1H, masked signal), 2.18-2.25 (2H, m), 1.84-1.90 (2H, m).MS m/z: 307.1 (M+H)⁺.

Example 11 Preparation of3-(24(2H-1,2,3-triazol-4-yl)amino)-5-chlorophenyl)-2,2-dimethylpropanoicacid (compound I-33) Step 1:-Ethyl3-(2-bromo-5-chloro-phenyl)-2,2-dimethyl-propanoate

To a solution of diisopropylamine (818 mg, 1.13 mL, 8.09 mmol) in THF(20 mL) cooled to −78° C. was added n-butyllithium (3.10 mL of 2.5 M inhexanes, 7.74 mmol) over 5 min keeping temp below −70° C. On completeaddition the mixture was allowed to warm to 0° C. then cooled back to−78° C. Ethyl 2-methylpropanoate (817 mg, 940 μL, 7.03 mmol) was addedand the mixture stirred at below −70° C. for 45 min. A solution of1-bromo-2-(bromomethyl)-4-chloro-benzene (2.00 g, 7.03 mmol) in THF (10mL) was added and the reaction allowed to warm slowly to roomtemperature overnight. The mixture was quenched with saturated aqueousammonium chloride solution and extracted with EtOAc (3×). The combinedorganics were washed sequentially with water (3×) and brine (1×), dried(MgSO₄), and concentrated. Material was purified by flash columnchromatography eluting with 2.5% ether in hexanes to afford the titlecompound 6h as a colourless oil (747 mg, 32%). ¹H NMR (500 MHz, d6-DMSO)δ 7.63-7.65 (1H, m), 7.25-7.28 (2H, m), 4.09 (2h, q), 3.04 (2H, s),1.17-1.20 (9H, m).

Step2:-3-(2-((1-Benzyl-1H-1,2,3-triazol-5-yl)amino)-5-chlorophenyl)propanoicacid

To a mixture of 1-benzyl-1H-1,2,3-triazol-5-amine 5a (100 mg, 0.57mmol),chloro[2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl)]palladium(II)(4.0 mg, 0.0057 mmol),2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (2.4 mg, 0.0057mmol) and sodium tert-butoxide (116 mg, 1.21 mmol) under a nitrogenatmosphere was added ethyl3-(2-bromo-5-chloro-phenyl)-2,2-dimethyl-propanoate 6h (220 mg, 0.69mmol) and t-BuOH (4.5 mL). The reaction mixture was degassed byvacuum/nitrogen cycles (3×) and then heated to reflux for 1 h. Thereaction mixture was concentrated and the residue was treated withwater, acidified with 5% citric acid and extracted with EtOAc (3×). Thecombined organics were washed with brine (2×), dried (MgSO₄), andconcentrated. Material was purified by ISCO (0-50% EtOAc/hexanes) toafford the title 7h compound as an orange foam (85 mg, 39%). MS m/z:385.2 (M+H)⁺.

Step3:-3-(2-((2H-1,2,3-Triazol-4-yl)amino)-5-chlorophenyl)-2,2-dimethylpropanoicacid

To a solution of3-(2-((1-benzyl-1H-1,2,3-triazol-5-yl)amino)-5-chlorophenyl)propanoicacid 7h (85 mg, 0.22 mmol) in toluene (3.5 mL) was added aluminiumtrichloride (165 mg, 1.24 mmol) and the mixture heated at 100° C. for 1h. The mixture was allowed to cool to room temperature and diluted withwater and EtOAc followed by 5% citric acid solution. The aqueous wasfurther extracted with EtOAc and the combined organics washed withbrine, dried (MgSO₄), and concentrated. Material was purified by ISCO(0-60% EtOAc/hexanes) to afford the title compound I-33 as an off whitesolid (36 mg, 38%). ¹H NMR (500 MHz, d6-DMSO) δ 14.14 (1H, brs), 12.37(1H, brs), 7.84 (1H, brs), 7.60-7.63 (1H, m), 7.38-7.41 (1H, m), 7.14(1H, d), 7.08 (1H, d), 2.77 (1H, d), 2.67 (1H, d), 1.12 (6H, s). MS m/z:295.1 (M+H)⁺.

The following aminotriazoles were synthesised using a similar procedureas outlined for compound I-33: Compounds I-31, I-32, and I-35

Analytical Data Cmpd LCMS LCMS No. ES + (Rt min) HNMR I-1 223.0 0.82 1HNMR (500 MHz, DMSO) δ 7.78 (br s, 1H), 7.59 (br s, 1H), 7.47 (s, 1H),7.14-7.10 (m, 2H), 2.65 (q, J = 7.5 Hz, 2H), 1.17 (t, J = 7.5 Hz, 3H).I-2 195.0 0.69 1H NMR (500 MHz, DMSO) δ 14.17 (s, 1H), 8.93 (s, 1H),7.39-7.30 (m, 3H), 7.25 (d, J = 8.4 Hz, 2H). I-3 240.9 0.71 1H NMR (500MHz, DMSO) δ 8.79 (s, 1H), 7.42-7.24 (m, 3H), 7.26-7.16 (m, 2H). I-4239.0 0.74 1H NMR (500 MHz, DMSO) δ 14.35 (brs, 1H), 7.72 (s, 1H),7.62-7.55 (m, 1H), 7.56-7.49 (m, 1H), 7.33-7.19 (m, 2H), 5.76 (s, 2H),4.50 (s, 3H). I-5 209.0 0.76 1H NMR (500 MHz, DMSO) δ 7.42 (d, 1H), 7.37(s, 1H), 7.29 (s, 1H), 7.10 (d, 1H), 7.05 (dd, 1H), 2.22 (s, 3H) I-6253.1 0.77 1H NMR (500 MHz, DMSO) δ 14.1-13.94 (br s, 1H), 7.86 (s, 1H)7.62-7.44 (m, 2H), 7.17-7.13 (m, 2H), 3.58-3.55 (m, 2H), 3.28 (s, 3H),2.90-2.88 (m, 2H). I-7 223.1 0.82 1H NMR (500 MHz, DMSO-d6) δ 8.79 (s,1H), 7.42 (s, 1H), 7.26-7.20 (m, 2H), 7.15-7.11 (m, 1H), 2.64 (q, J =7.5 Hz, 2H), 1.17 (t, J = 7.5 Hz, 3H). I-8 225.0 0.68 1H NMR (500 MHz,DMSO) δ 8.67 (s, 1H) 7.30 (s, 1H) 7.20 (d, 1H), 7.10 (s, 1H) 6.75 (d,1H), 3.72 (s, 3H). I-9 225.1 0.59 1H NMR (500 MHz, DMSO) δ 14.20 (s,1H), 7.85-7.80 (s, 1H), 7.60 (s, 1H), 7.51 (s, 1H), 7.31 (d, J = 2.6 Hz,1H), 7.19 (dd, J = 8.7, 2.7 Hz, 1H), 4.55 (s, 2H). I-10 324.0 0.72 1HNMR (500 MHz, DMSO) δ 14.23 (brs, 1H), 7.81 (s, 1H), 7.71 (d, J = 8.7Hz, 1H), 7.52 (s, 1H), 7.09 (d, J = 2.4 Hz, 1H), 6.92 (dd, J = 8.6, 2.3Hz, 1H), 4.20 (t, J = 5.9 Hz, 2H), 3.62-3.56 (m, 4H), 3.42-3.24 (m, 4H),2.77 (t, J = 5.9 Hz, 2H). I-11 195.0 0.69 1H NMR (500 MHz, DMSO) δ 8.66(s, 1H), 7.34-7.21 (m, 2H), 7.18-7.16 (m, 1H), 7.06 (d, 1H), 6.69 (d,1H). I-12 225.1 0.76 1H NMR (500 MHz, DMSO) δ 7.67 (d, J = 8.7 Hz, 1H),7.61 (br s, 1H), 7.33 (s, 1H), 6.96 (d, J = 2.3 Hz, 1H), 6.87 (dd, J =8.6, 2.3 Hz, 1H), 3.88 (s, 3H). I-13 213.0 0.71 1H NMR (500 MHz, DMSO) δ8.74 (s, 1H), 7.50 (dd, 1H), 7.31 (s, 1H), 7.23 (dd, 1H), 7.13-7.10 (m,1h) I-14 213.0 0.72 1H NMR (500 MHz, DMSO) δ 9.07 (s, 1H), 7.40 (s, 1H),7.36-7.32 (m, 2H), 7.02 (dd, 1H) I-15 223.1 0.78 1H NMR (500 MHz, DMSO)δ 7.26-7.25 (br m, 1H), 7.11 (br s, 2H), 6.85 (br m, 1H), 3.18 (s, 1H),2.12 (s, 6H). I-16 229.0 0.85 1H NMR (500 MHz, DMSO) δ 9.20 (s, 1H),7.48-7.45 (m, 1H), 7.44-7.25 (m, 2H), 6.91 (s, 1H). I-17 316.0 0.65 1HNMR (500 MHz, MeOD) δ 7.41 (s, 2H), 7.25 (d, J = 2.5 Hz, 1H), 7.16 (dd,J = 8.7, 2.5 Hz, 1H), 3.39-3.32 (m, 2H), 3.15-3.08 (m, 2H), 2.70 (s,3H). I-18 259.0 0.73 1H NMR (500 MHz, DMSO) δ 14.18 (s, 1H), 8.96 (d, J= 7.1 Hz, 1H), 7.71 (s, 1H), 7.36 (s, 1H), 7.24 (d, J = 6.7 Hz, 2H).I-19 229.0 0.78 1H NMR (500 MHz, DMSO) δ 13.79 (brs, 1H), 9.14 (s, 1H),7.63 (1H, s), 7.44-7.42 (m, 2H), 7.21 (d, 1H) I-20 266.1 0.62 1H NMR(500 MHz, DMSO) δ 8.53 (t, J = 6.1 Hz, 1H), 8.36-8.32 (m, 1H), 7.61 (d,J = 8.6 Hz, 1H), 7.44 (s, 1H), 7.25-7.15 (m, 2H), 4.28 (d, J = 6.2 Hz,2H), 1.93 (s, 3H). I-21 302.1 0.62 1H NMR (500 MHz, DMSO) δ 7.77 (s,1H), 7.54 (d, J = 8.7 Hz, 1H), 7.47 (s, 1H), 7.33 (d, J = 2.6 Hz, 1H),7.23 (dd, J = 8.7, 2.6 Hz, 1H), 4.21 (s, 2H), 2.97 (s, 3H). I-22 196.00.49 1H NMR (500 MHz, DMSO) δ 14.28 (s, 1H), 9.19 (s, 1H), 8.38 (s, 1H),8.83 (d, 1H), 7.42 (s, 1H), 7.35 (d, 1H). I-23 338.0 0.96 1H NMR (500MHz, DMSO) δ 8.16 (s, 1H), 7.63 (s, 1H), 7.40 (s, 1H), 7.23 (d, J = 8.5Hz, 1H), 7.16 (s, 1H), 4.41 (s, 2H), 2.80 (s, 3H), 1.47-1.36 (m, 9H).I-24 179.0 0.6 1H NMR (500 MHz, DMSO) δ 8.28 (brs, 1H), 7.20 (s, 1H),7.18-7.14 (m, 2H), 7.01-6.96 (m, 2H). I-25 321.0 0.81 1H NMR (500 MHz,CDCl3) δ 7.76 (d, 1H), 7.50 (s, 1H), 7.44 (d, 1H), 7.29 (s, 1H), 7.26(dd, 1H). I-26 265.9 0.59 1H NMR (500 MHz, DMSO) δ 15.58 (brs, 1H), 8.56(s, 1H), 8.07 (d, 1H), 7.79-7.68 (m, 3H). I-27 229.1 0.78 1H NMR (500MHz, DMSO) δ 8.22 (br s, 1H), 7.81-7.79 (m, 1H), 7.58 (s, 1H), 7.51 (d,J = 2.5 Hz, 1H), 7.29 (dd, J = 8.9, 2.5 Hz, 1H). I-28 307.1 0.50 1H NMR(500 MHz, DMSO) δ 7.78 (br s, 1H), 7.59 (br s, 1H), 7.46 (br s, 1H),7.12-7.10 (m, 1H), 7.06 (d, J = 2.6 Hz, 1H), 2.94-2.87 (m, 1H), 2.72 (d,J = 7.3 Hz, 2H), 2.55-2.50 (1H, masked signal), 2.25-2.18 (m, 2H),1.90-1.84 (m, 2H). I-29 195.0 0.67 1H NMR (500 MHz, DMSO) δ 8.05 (s,1H), 7.79 (1H, d), 7.59 (s, 1H), 7.40 (d, 1H), 7.24-7.21 (m, 1H),6.84-6.80 (m, 1H). I-30 213.0 0.72 1H NMR (500 MHz, DMSO) δ 14.24 (brs,1H), 8.71 (s, 1H), 9.94 (s, 1H), 7.45 (s, 1H), 7.35 (d, 1H), 7.18 (d,1H). I-31 267.0 0.45 1H NMR (500 MHz, DMSO) δ 14.18 (s, 1H), 12.18 (s,1H), 7.96 (s, 1H), 7.74-7.35 (m, 2H), 7.20-7.00 (m, 2H), 2.87 (t, J =7.6 Hz, 2H), 2.56 (d, J = 12.4 Hz, 2H). I-32 309.1 0.56 1H NMR (500 MHz,DMSO) δ 14.21 (br s, 1H), 12.16 (br s, 1H), 7.77 (br s, 1H), 7.49-7.43(br m, 2H), 7.13-7.09 (m, 2H), 2.83-2.81 (m, 2H), 1.92 (sextet, J =13.3, 6.7 Hz, 1H), 1.25 (br s, 1H), 0.98 (dd, J = 13.7, 6.8 Hz, 6H).I-33 295.1 0.61 1H NMR (500 MHz, DMSO) δ 14.14 (br s, 1H), 12.37 (br s,1H), 7.84 (br s, 1H), 7.63-7.60 (br m, 1H), 7.41-7.38 (br m, 1H), 7.14(d, J = 8.3 Hz, 1H), 7.08 (d, J = 2.6 Hz, 1H), 2.77 (d, J = 15.4 Hz,1H), 2.67 (d, J = 15.4 Hz, 1H), 1.12 (s, 6H). I-34 224.1 0.57 1H NMR(500 MHz, DMSO) δ 8.46 (brs, 4H), 7.64 (d, 1H), 7.53 (s, 1H), 7.48 (d,1H), 7.32 (dd, 1H), 4.14-4.10 (m, 2H). I-35 323.2 0.59 1H NMR (500 MHz,DMSO) δ 14.18 (br s, 1H), 12.12 (br s, 1H), 7.65 (br s, 1H), 7.50-7.37(br m, 2H), 7.14-7.10 (m, 2H), 2.88 (d, J = 14.7 Hz, 1H), 2.80-2.75 (m,1H), 2.47-2.46 (m, 1H), 1.03 (s, 9H). I-36 193.0 0.68 1H NMR (500 MHz,DMSO) δ 7.76-7.48 (m, 2H), 7.39 (s, 1H), 6.99 (ddd, J = 9.5, 3.1, 0.9Hz, 1H), 6.91 (dddd, J = 9.0, 8.4, 3.1, 0.7 Hz, 1H), 2.25 (t, J = 0.6Hz, 3H). I-37 241.0 0.77 1H NMR (500 MHz, DMSO) δ 14.20 (brs, 1H), 8.95(s, 1H), 7.58 (s, 1H), 7.42 (d, 1H), 7.20-7.15 (m, 2H), 6.93 (d, 1H).I-38 209.0 0.79 1H NMR (500 MHz, DMSO-d6) δ 14.13 (s, 1H), 9.00-8.52 (m,1H), 7.70-6.70 (m, 3H), 2.28 (s, 3H). I-39 209.0 0.75 1H NMR (500 MHz,DMSO-d6) δ 14.19 (s, 1H), 7.87 (s, 1H), 7.47 (m, 2H), 7.08 (t, J = 8.1Hz, 1H), 6.96-6.81 (m, 1H), 2.31 (s, 3H). I-40 221.1 0.81 1H NMR (500MHz, DMSO) δ 14.17 (s, 1H), 8.16 (s, 1H), 7.65 (s, 1H), 7.47 (d, J = 2.5Hz, 1H), 7.5 (s, 1H), 7.22 (m, J = 7.5 Hz, 1H), 7.05 (dd, J = 17.2, 11.0Hz, 1H), 5.80 (dd, J = 17.2, 1.2 Hz, 1H), 5.36 (dd, J = 10.9, 1.2 Hz,1H). I-41 209.0 0.76 1H NMR (500 MHz, DMSO-d6) δ 14.23 (s, 1H), 8.92 (s,1H), 7.45 (s, 1H), 7.27 (s, 1H), 7.01 (s, 1H), 6.68 (s, 1H), 2.29 (m,3H). I-42 209.1 0.79 1H NMR (500 MHz, DMSO-d6) δ 14.21 (s, 1H), 7.93 (s,1H), 7.79 (s, 1H), 7.50 (s, 1H), 7.11 (m, 1H), 6.87-6.54 (m, 1H), 2.24(s, 3H). I-43 330.1 0.75 1H NMR (500 MHz, DMSO) δ 7.93 (br s, 1H), 7.48(br s, 1H), 7.43 (br s, 1H), 7.27 (d, J = 2.5 Hz, 1H), 7.18 (dd, J =8.7, 2.6 Hz, 1H), 3.37-3.34 (m, 2H), 3.06-3.02 (m, 2H), 2.80 (s, 6H).I-44 220.0 0.68 1H NMR (500 MHz, DMSO-d6) δ 14.45 (s, 1H), 9.33 (s, 1H),7.80 (s, 1H), 7.65-7.39 (m, 3H). I-45 179.1 0.63 1H NMR (500 MHz,DMSO-d6) δ 14.19 (s, 1H), 9.02 (s, 1H), 7.39 (d, J = 1.9 Hz, 1H),7.27-7.17 (m, 2H), 7.06-6.99 (m, 1H), 6.61-6.52 (m, 1H). I-46 308.1 0.781H NMR (500 MHz, DMSO) δ 14.29 (br s, 1H), 9.93 (br s, 1H), 7.89 (br s,1H), 7.50 (br s, 2H), 7.26 (d, J = 2.5 Hz, 1H), 7.22 (dd, J = 8.7, 2.6Hz, 1H), 4.05 (d, J = 12 Hz, 2H), 3.75-3.66 (masked signal, 2H), 3.53(d, J = 12 Hz, 2H), 3.38 (t, J = 8.2 Hz, 2H), 3.17-3.15 (m, 2H),3.08-3.05 (m, 2H). I-47 322.1 0.79 1H NMR (500 MHz, DMSO) δ 10.22 (br s,1H), 7.88 (br s, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.49 (s, 1H), 7.20 (d, J= 2.6 Hz, 1H), 7.15 (dd, J = 8.7, 2.6 Hz, 1H), 3.98 (d, J = 11.5 Hz,2H), 3.67 (t, J = 12.2 Hz, 2H), 3.46 (d, J = 12.2 Hz, 2H), 3.19-3.15 (m,2H), 3.11-3.04 (m, 2H), 2.71 (t, J = 7.8 Hz, 2H), 1.99-1.93 (m, 2H).I-48 339.1 0.68 1H NMR (500 MHz, DMSO) δ 7.86 (br s, 1H), 7.69 (br s,1H), 7.55 (br s, 1H), 7.10 (d, J = 2.3 Hz, 1H), 6.95 (dd, J = 8.7, 2.3Hz, 1H), 4.31 (t, J = 5.0 Hz, 2H), 3.69-2.95 (masked signals, 6H), 2.81(s, 3H), 2.53-2.50 (masked signal, 4H).

IDO1 Assay

The compounds of the present invention are evaluated as inhibitors ofIDO1 using the following assay.

Example 12 Cellular IDO1 Inhibition Assay

Compounds can be screened for their ability to inhibit intracellularIDO1 activity, by measuring the production of L-kynurenine by HeLa cellsin which IDO1 expression is induced by IFN-γ. Kynurenine levels can bedetermined by chemical conversion of L-kynurenine with Ehrlich's reagent(Yue et. al., J Med Chem 2009 Dec. 10; 52(23):7364-7).

HeLa cells were plated at 20,000 cells per well in 96-well cultureplates (Costar 3598) in DMEM (Sigma D5671) supplemented with 10% fetalbovine serum (SAFC Biosciences 12003C), Penicillin/Streptomycin solutiondiluted 1:100 (Sigma P7539), 4 mM L-glutamine (Sigma G7513), 1% NonEssential Aminoacids (Sigma M7145) and 1 mM Sodium Pyruvate (SigmaS8636). Cells were allowed to adhere for 24 hours at 37° C. in 5% CO₂.Subsequently compounds were first serially diluted 1/3 in DMSO thenfurther diluted in media and finally added to the cells, giving amaximal final concentration of 40 μM. Additional medium containingL-tryptophan to a final concentration of 250 μM (Sigma T0254) and humanrecombinant IFN-γ (R&D Systems 285-IF) were added to the wells tostimulate IDO1 production. Cells were incubated at 37° C. in 5% CO₂ for48 hours.

For the measurement of L-kynurenine in HeLa supernatants, plates werecentrifuged at 1000 RPM for 5 minutes and 140 μl of media transferredinto a polypropylene 96 well plate (Costar 3879) containing 10 μl of 26%Trichloroacetic Acid in water (Sigma T9159). Plates were then sealedusing a plate sealer (PlateLoc, Agilent Technology) and incubated at 50°C. for 30 minutes. Plates were centrifuged at 2400 RPM for 10 minutesand 100 μl of media transferred to polystyrene 96-well plates togetherwith 100 μl of Ehrlich's reagent (2% p-Dimethylaminobenzaldehyde, (SigmaD2004) in acetic acid (Fisher, A/400/PB17)). Following the addition ofEhrlich's reagent the absorbance at 490 nm was read using aspectrophotometer (Spectramax Plus, Molecular Devices). Kynureninelevels were plotted against compound concentrations to generate doseresponse curves and obtain 1050 values for each active compound usingGenedata Screener® Software.

Cellular 1050 values for each compound may be found in Table 2, below,wherein A=<0.1 μM; B=0.1 μM-1 μM; and C=1 μM-40 μM.

TABLE 2 Cellular Assay Cmpd No. IC50 Values (μM) I-1 A I-2 A I-3 A I-4 AI-5 A I-6 A I-7 B I-8 B I-9 B I-10 B I-11 B I-12 B I-13 B I-14 B I-15 BI-16 B I-17 B I-18 B I-19 B I-20 B I-21 C I-22 C I-23 C I-24 B I-25 CI-26 — I-27 C I-28 C I-29 C I-30 C I-31 C I-32 C I-33 C I-34 C I-35 CI-36 A I-37 B I-38 B I-39 B I-40 A I-41 B I-42 A I-43 B I-44 B I-45 BI-46 B I-47 B I-48 B

Example 13 Cellular Viability Assay

To ensure that reduction in IDO1 activity was not caused by non-specificcytotoxicity of a given compound, cell viability of stimulated HeLacells after incubation with compound was assessed by measuringmitochondrial function using3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium,inner salt assay (MTS; Promega G3581). For the MTS viability assay 5,000HeLa cells per well were seeded and treated as described in example 12.After 48 hour incubation, cell plates were removed from the 37° C.incubator and 40 μl of Cell Titer 96 Aqueous solution (Promega, G358B)added to each well. Cells were incubated for 1 hour at 37° C. in 5% CO₂and absorbance read at 490 nm in the spectrophotometer. Absorbancevalues were plotted against compound concentrations to generate doseresponse curves and obtain IC50 values for each compound using GenedataScreener® Software.

While we have described a number of embodiments of this invention, it isapparent that our basic examples may be altered to provide otherembodiments that utilize the compounds, methods, and processes of thisinvention. Therefore, it will be appreciated that the scope of thisinvention is to be defined by the appended claims rather than by thespecific embodiments that have been represented by way of exampleherein.

1. A compound of formula I-A:

or a pharmaceutically acceptable salt or prodrug thereof, wherein: n is0-4; X is halo; Z¹, Z², and Z³ are CH or N; R¹ is independently selectedfrom halo; —CN; Q^(X); or a C₁₋₁₀aliphatic chain wherein up to fourmethylene units of the aliphatic chain are optionally replaced with —O—,—NR—, —S—, —C(O)—, S(O)—, or —S(O)₂—; R¹ is optionally substituted with0-5 J¹ groups; Q^(X) is a 3-7 membered monocyclic fully saturated,partially unsaturated, or aromatic ring containing 0-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; J¹ isindependently selected from halo; —CN; Q^(Y); or a C₁₋₆aliphatic chainwherein up to three methylene units of the aliphatic chain areoptionally replaced with —O—, —NR—, —S—, —C(O)—, S(O)—, or —S(O)₂—; J¹is optionally substituted with 0-5 J² groups; or two occurrences of J¹on the same atom, together with the atom to which they are attached,form a 3-6 membered non-aromatic monocyclic ring; the ring formed by twooccurrences of J¹ on the same atom is optionally substituted with 0-3J^(2A) groups; or two occurrences of J¹, together with Q^(X), form abridged ring system; Q^(Y) is independently selected from a 3-7 memberedmonocyclic fully saturated, partially unsaturated, or aromatic ringcontaining 0-3 heteroatoms independently selected from nitrogen, oxygen,or sulfur; or an 8-12 membered bicyclic fully saturated, partiallyunsaturated, or aromatic ring containing 0-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur; J² is independently selectedfrom halo; ═O; —CN; a 3-6 membered aromatic or non-aromatic ringcontaining 0-3 heteroatoms selected from oxygen, nitrogen, or sulfur; orC₁₋₄aliphatic chain wherein up to two methylene units of the aliphaticchain are optionally replaced with —O—, —NR—, —S—, —C(O)—, S(O)—, or—S(O)₂—; J² is optionally substituted with 0-5 J³ groups; or twooccurrences of J², together with the atom or atoms to which they areattached, form a 3-6 membered aromatic or non-aromatic monocyclic ring;the ring formed by two occurrences of J² is optionally substituted with0-3 J^(3A) groups; or two occurrences of J², together with Q^(Y), form abridged ring system; J^(2A) is independently selected from halo or aC₁₋₄aliphatic chain wherein up to two methylene units of the aliphaticchain are optionally replaced with —O—, —NR—, —S—, —S(O)—, —S(O)₂, or—C(O); J³ and J^(3A) are independently selected from halo or C₁₋₄alkyl;and R is independently selected from H or C₁₋₆aliphatic.
 2. The compoundof claim 1, wherein Z¹ and Z² are CH and Z³ is nitrogen.
 3. The compoundof claim 1, wherein Z¹ and Z³ are CH and Z² is nitrogen.
 4. The compoundof claim 1, wherein Z¹ and Z² are nitrogen and Z³ is CH.
 5. The compoundof claim 1, wherein Z¹, Z², and Z³ are CH.
 6. The compound of claim 1,wherein X is selected from bromo or chloro.
 7. The compound of claim 6,wherein X is bromo.
 8. The compound of claim 6, wherein X is chloro. 9.The compound of claim 8, wherein n is
 0. 10. The compound of claim 1,wherein R¹ is independently selected from halo, —CN, or a C₁₋₈aliphaticchain wherein up to four methylene units of the aliphatic chain areoptionally replaced with —O—, —NR—, —C(O)—, or —S(O)₂—.
 11. The compoundof claim 10, wherein R¹ is a C₁₋₆aliphatic chain wherein up to threemethylene units of the aliphatic chain are optionally replaced with —O—,—NR—, —C(O)—, or —S(O)₂—.
 12. The compound of claim 11, wherein R¹ isindependently selected from C₁₋₆alkyl, —(C₁₋₄alkyl)O(C₁₋₄alkyl),—NHSO₂(C₁₋₄alkyl), —(C₁₋₄alkyl)NHC(O)(C₁₋₄alkyl), —CO₂(C₁₋₄alkyl),—(C₁₋₄alkyl)NHSO₂(C₁₋₄alkyl), —(C₁₋₄alkyl)SO₂NH(C₁₋₄alkyl),—C(O)NH(C₁₋₄alkyl), —C(O)NH, —O(C₁₋₄alkyl),—(C₁₋₄alkyl)NHCO₂(C₁₋₄alkyl), —SO₂(C₁₋₄alkyl), —(C₁₋₄alkyl)CH(O),—(C₁₋₄alkyl)NH₂, —(C₁₋₄alkyl)OH, —(C₁₋₄alkyl)C(O)OH, or —C(O)NH₂. 13.The compound of claim 12, wherein R¹ is independently selected fromC₁₋₆alkyl, —(C₁₋₄alkyl)O(C₁₋₄alkyl), —(C₁₋₄alkyl)SO₂NH(C₁₋₄alkyl),—(C₁₋₄alkyl)NHC(O)(C₁₋₄alkyl), —(C₁₋₄alkyl)NHS 0₂(C₁₋₄alkyl),—(C₁₋₄alkyl)NHCO₂(C₁₋₄alkyl), or —O(C₁₋₄alkyl).
 14. The compound ofclaim 13, wherein R¹ is independently selected from C₁₋₆alkyl,—O(C₁₋₄alkyl), or —(C₁₋₄alkyl)O(C₁₋₄alkyl).
 15. The compound of claim10, wherein R¹ is —CN.
 16. The compound of claim 10, wherein R¹ is halo.17. The compound of claim 10, wherein J¹ is independently selected fromhalo, a C₁₋₆aliphatic, or Q^(Y).
 18. The compound of claim 17, whereinJ¹ is halo.
 19. The compound of claim 18, wherein J¹ is fluoro.
 20. Thecompound of claim 17, wherein J¹ is a C₁₋₆aliphatic.
 21. The compound ofclaim 20, wherein J¹ is a C₁₋₄alkyl.
 22. The compound of claim 17,wherein J¹ is Q^(Y).
 23. The compound of claim 22, wherein Q^(Y) isindependently selected from a 5-6 membered aryl or heteroaryl, a 3-7membered cycloaliphatic, or a 3-7 membered heterocyclyl; the heteroaryland heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen,or sulfur.
 24. The compound of claim 23, wherein Q^(Y) is independentlyselected from a 3-7 membered cycloaliphatic or a 3-7 memberedheterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, orsulfur.
 25. The compound of claim 24, wherein Q^(Y) is independentlyselected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, piperidinyl, azepanyl, pyrrolidinyl, piperazinyl,morpholinyl, thiomorpholinyl, pyrazolidinyl, isoxazolidinyl,thiazolidinyl, imidazolidinyl, 1,4-diazepanyl, 1,4-oxazepanyl,1,4-thiazepanyl, 1,3-oxazinanyl, or 1,3-thiazinanyl.
 26. The compound ofclaim 25, wherein Q^(Y) is independently selected from cyclobutyl,piperazinyl, or morpholinyl.
 27. The compound of claim 23, wherein Q^(Y)is a 5-6 membered aryl or heteroaryl.
 28. The compound of claim 27,wherein Q^(Y) is independently selected from phenyl, pyrrolyl,pyridinyl, isoxazolyl, pyrimidinyl, imidazolyl, pyrazinyl, or pyrazolyl.29. The compound of claim 28, wherein Q^(Y) is phenyl.
 30. The compoundof claim 17, wherein J² is halo.
 31. The compound of claim 17, whereinJ² is a 3-6 membered aromatic or non-aromatic monocyclic ring having 1-3heteroatoms selected from oxygen, nitrogen, or sulfur.
 32. The compoundof claim 31, wherein J² is independently selected from cyclopropyl,cyclobutyl, or phenyl.
 33. The compound of claim 17, wherein J² isindependently selected from a C₁₋₄aliphatic chain wherein up to twomethylene units of the aliphatic chain are optionally replaced with —O—,—NR—, —S—, —C(O)—, S(O)—, or —S(O)₂—.
 34. The compound of claim 33,wherein J² is —C(O)OH or —C₁₋₄alkyl.
 35. The compound of claim 1 havingthe formula:

or a pharmaceutically acceptable prodrug thereof, wherein X is bromo orchloro.
 36. The compound of claim 35, wherein Z¹ and Z² are nitrogen.37. The compound of claim 35, wherein only one of Z¹ or Z² is nitrogen.38. The compound of claim 35, wherein Z¹ and Z² are CH.
 39. The compoundof claim 35, wherein X is chloro.
 40. The compound of claim 39, whereinn is
 0. 41. The compound of claim 35, wherein R¹ is independentlyselected from halo, —CN, or a C₁₋₈aliphatic chain wherein up to fourmethylene units of the aliphatic chain are optionally replaced with —O—,—NR—, —C(O)—, or —S(O)₂—.
 42. The compound of claim 41, wherein R¹ is aC₁₋₆aliphatic chain wherein up to three methylene units of the aliphaticchain are optionally replaced with —O—, —NR—, —C(O)—, or —S(O)₂—. 43.The compound of claim 42, wherein R¹ is independently selected fromC₁₋₆alkyl, —(C₁₋₄alkyl)O(C₁₋₄alkyl), —(C₁₋₄alkyl)OH, —O(C₁₋₄alkyl),—(C₁₋₄alkyl)SO₂NH(C₁₋₄alkyl), —(C₁₋₄alkyl)NHC(O)(C₁₋₄alkyl),—(C₁₋₄alkyl)NHSO₂ (C₁₋₄alkyl), —(C₁₋₄alkyl)NHCO₂(C₁₋₄alkyl), or—(C₁₋₄alkyl)C(O)OH.
 44. The compound of claim 43, wherein R¹ isindependently selected from C₁₋₆alkyl, —O(C₁₋₄alkyl), or—(C₁₋₄alkyl)O(C₁₋₄alkyl).
 45. The compound of claim 41, wherein R¹ is—CN.
 46. The compound of claim 41, wherein R¹ is halo.
 47. The compoundof claim 41, wherein J¹ is independently selected from halo, aC₁₋₆aliphatic, or a 3-7 membered aromatic or non-aromatic ringcontaining 0-4 heteroatoms independently selected from nitrogen, oxygen,or sulfur.
 48. The compound of claim 47, wherein J¹ is a C₁₋₆aliphatic.49. The compound of claim 48, wherein J¹ is a C₁₋₄alkyl.
 50. Thecompound of claim 47, wherein J¹ is a 3-6 membered cycloaliphatic or a3-6 membered heterocyclyl having 1-2 heteroatoms selected from oxygen,nitrogen, or sulfur.
 51. The compound of claim 50, wherein J¹ isindependently selected from cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, orthiomorpholinyl.
 52. The compound of claim 51, wherein J¹ isindependently selected from cyclobutyl, piperazinyl, or morpholinyl. 53.A compound selected from:


54. A composition comprising a compound of any one of claim 1 or 53, anda pharmaceutically acceptable carrier, adjuvant, or vehicle. 55-63.(canceled)